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US20090269774A1 - Evaluation of eosinophilic esophagitis - Google Patents

Evaluation of eosinophilic esophagitis Download PDF

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US20090269774A1
US20090269774A1 US12/492,456 US49245609A US2009269774A1 US 20090269774 A1 US20090269774 A1 US 20090269774A1 US 49245609 A US49245609 A US 49245609A US 2009269774 A1 US2009269774 A1 US 2009269774A1
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Marc E. Rothenberg
Carine Blanchard
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Cincinnati Childrens Hospital Medical Center
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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/16—Primer sets for multiplex assays
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • the invention is directed generally to evaluating and mitigating eosinophilic esophagitis.
  • Patients with eosinophilic esophagitis may have symptoms that include abdominal pain, difficulty swallowing, vomiting, failure to thrive and weight loss.
  • allergy particularly food allergy, is an associated finding in most patients, and many have concomitant asthma or other chronic respiratory disease. Diagnosis requires endoscopy, and diseased tissue shows characteristic punctate white surface dots associated with erythema, loss of vascular pattern, ulcers, or ringed trachea-like appearance.
  • Eosinophils are one type of granulocytic leukocyte (white blood cell) or granulocyte that normally appears in the peripheral blood at a concentration of about 1-3% of total leukocytes. Their presence in tissues is normally primarily restricted to the gastrointestinal mucosa, i.e. the stomach and intestines. Eosinophil accumulation in the peripheral blood and tissues is a hallmark feature of an allergic response, and may cause potent pro-inflammatory effects or tissue remodeling.
  • Eosinophil accumulation occurs in other allergic diseases such as allergic rhinitis, asthma, and eczema as well as parasitic infections, certain types of malignancies, chronic inflammatory disorders such as inflammatory bowel disease, specific syndromes such as eosinophilic gastroenteritis, eosinophilic colitis, eosinophilic cellulitis, eosinophilic fascitis, and systemic diseases such as Churg Strauss syndrome, eosinophilic pneumonia, and the idiopathic hypereosinophilic syndrome.
  • mediators have been identified as eosinophil chemoattractants. These include diverse molecules such as lipid mediators (platelet activating factor (PAF), leukotrienes) and chemokines such as the eotaxin subfamily of chemokines. Chemokines are small secreted proteins produced by tissue cells and leukocytes that regulate leukocyte homing during homeostatic and inflammatory states. Two main subfamilies (CXC and CC chemokines) are distinguished depending upon the arrangement of the first two cysteine amino acids, either separated by one amino acid (CXC), or adjacent (CC).
  • CXC cysteine amino acids
  • eosinophilic esophagitis Due to the increasing incidence of eosinophilic esophagitis, methods to mitigate eosinophilic esophagitis would be beneficial. In addition, because eosinophilic esophagitis is often confused with other disorders such as gastroesophageal reflux disease (GERD), but does not typically respond to anti-GERD therapy, it is important to develop diagnostic features that distinguish between eosinophilic esophagitis and GERD. Diagnosis currently requires endoscopy with subsequent biopsy and analysis of the excised tissue by a pathologist based on manual microscopic analysis, so that less invasive methods of diagnosing eosinophilic esophagitis would also be beneficial.
  • GSD gastroesophageal reflux disease
  • normal individuals individuals without eosinophilic esophagitis (EE), control group or controls, patients without EE, and normal patients are used synonymously.
  • One embodiment of the invention is a method of assessing eosinophilic esophagitis (EE) in a patient by comparing the patient's blood concentration of eotaxin-3 to a normal concentration of eotaxin-3, where an increased concentration of eotaxin-3 indicates EE.
  • EE eosinophilic esophagitis
  • Another embodiment of the invention is a diagnostic assay for EE.
  • One embodiment of the assay may include a test strip containing an anti-eotaxin-3 antibody and at least one reagent that indicates binding of the anti-eotaxin-3 antibody to eotaxin-3 present in a supranormal level in a biological sample. Detection may be by visual inspection for a chromogen, fluorogen, colloidal gold agglutination, luminescence, etc.
  • Another embodiment of the invention is a diagnostic method for EE where eotaxin-3 DNA, eotaxin-3 mRNA, and/or eotaxin-3 protein is present over a normal amount in a patient tissue, as an indicator of EE in the patient.
  • Another embodiment of the invention is a diagnostic method for EE where a frequency of single nucleotide polymorphisms (SNPs) in the eotaxin-3 gene above normal frequency is an indicator of EE or a marker of disease risk, prognosis, and/or a response to therapy.
  • SNPs single nucleotide polymorphisms
  • Another embodiment of the invention is a method to mitigate EE by providing an inhibitor to eotaxin-3 and/or a receptor, such as CCR3, for binding eotaxin-3 in a cell, such as a mast cell or an eosinophil, under conditions sufficient to inhibit eotaxin-3 binding to the receptor.
  • a receptor such as CCR3
  • Another embodiment of the invention is a gene expression profile for EE comprising SEQ. ID NOS. 1-1620.
  • Another embodiment of the invention is a method to evaluate EE by gene expression profiles, where evaluation encompasses assessment of disease propensity, of disease severity, of therapy efficacy, of therapy compliance, etc.
  • EE is evaluated by determining an expression profile of at least one gene in the esophagus of the patient, where the gene is selected from SEQ ID NOS. 1-1620.
  • EE is evaluated by determining an expression profile of at least one gene in the patient, where the gene is selected from group consisting of SEQ ID NOS. 1-1620. The expression profile of the selected gene(s) is then compared to the expression profile of that same gene in an individual that does not have EE.
  • the patient's propensity for EE is evaluated by determining if the gene in the patient is either over-expressed ⁇ 1.5 times or is under-expressed ⁇ 1.5 times compared to the same gene in the expression profile in the individual without EE. This propensity is evaluated by determining the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed.
  • the patient's propensity for EE is higher based on at least one of the farther the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are over-expressed or under-expressed.
  • the gene is SEQ ID NO.1.
  • the patient lacks at least one clinical and/or physical symptoms of EE.
  • the cell is an esophageal cell.
  • Another embodiment of the invention is a method to evaluate a compound's contribution to the pathophysiology of EE.
  • At least one cell referred to as the test cell, is exposed to the compound, and an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in the cell(s) is compared to an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in a cell of an individual without EE, referred to as the control cell.
  • the contribution of the compound to the pathophysiology of EE is evaluated by determining if the at least one gene in the test cell is either over-expressed ⁇ 1.5 times or is under-expressed ⁇ 1.5 times compared to the same gene in the expression profile of the control cell.
  • the compound's contribution to the pathophysiology of EE is evaluated by determining the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed.
  • the compound contributes more to the pathophysiology of EE based on at least one of the farther the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are over-expressed or under-expressed.
  • the cell is an esophageal cell.
  • therapeutics that antagonize the action of the compound may be used to treat EE.
  • Another embodiment of the invention is a method to evaluate an individual's response to therapy for EE.
  • An expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in an esophagus of an individual exposed to therapy is compared to an expression profile of the same gene(s) from an individual without EE.
  • the individual's response to therapy for EE is evaluated by determining if the at least one gene is either over-expressed ⁇ 1.5 times or is under-expressed ⁇ 1.5 times compared to the same gene in the expression profile from the individual without EE.
  • the individual's response to therapy for EE is evaluated based on the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed.
  • the individual is less responsive to therapy for EE based on at least one of the farther the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are expressed or under-expressed.
  • Another embodiment of the invention is a method to evaluate an individual's compliance with therapy for EE.
  • An expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in an esophagus of an individual prescribed therapy for EE is compared to an expression profile of the same gene(s) from an individual without EE.
  • the individual's compliance with therapy is evaluated by determining if the at least one gene is either over-expressed ⁇ 1.5 times or is under-expressed ⁇ 1.5 times compared to the same gene in the expression profile from the individual without EE.
  • the individual's compliance with therapy is determined based on the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed.
  • the individual is less compliant with therapy for EE based on at least one of the father the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are over-expressed or under-expressed. That is, the gene expression is more like an individual with EE than a normal EE without EE.
  • Another embodiment of the invention is a method to evaluate whether an individual had EE prior to a current assessment.
  • An expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 6, 35, 43, 61, 129, 1358, 1441, 1515, 1538, 1584, 1615, 1618, and 1620 in an esophagus of an individual is compared to the expression profile of the same gene(s) from an individual without EE.
  • the individual's prior EE is evaluated by determining if the at least one gene is either over-expressed ⁇ 1.5 times or is under-expressed ⁇ 1.5 times compared to the same gene in the expression profile from the individual without EE.
  • the likelihood of the individual having EE prior to the current assessment is determined based on the extent that over-expression or under-expression exceeds 1.5, the identity of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed.
  • the individual is more likely to have had prior EE based on at least one of the farther the over-expression or under-expression is from 1.5, and/or the greater the number of genes that are over-expressed or under-expressed.
  • the individual does not have active EE when the method is performed.
  • FIG. 1 shows DNA microarray data of eotaxin-3 mRNA levels in esophageal tissue of normal patients and patients with eosinophilic esophagitis (EE).
  • FIG. 2 shows data from quantitative polymerase chain reaction analysis showing normalized eotaxin-3 mRNA levels in normal patients, patients with gastroesophageal reflux disease (GERD), and patients with EE.
  • GFD gastroesophageal reflux disease
  • FIG. 3 shows esophageal eosinophil concentration in control and allergen-induced wild-type mice, and allergen-induced mice lacking the gene encoding the CCR3 receptor.
  • FIG. 4 shows plasma concentrations of eotaxin-3 in normal patients and patients with EE.
  • FIG. 5 shows hierarchical cluster analysis of transcripts expressed in normal (NL), reflux (RE), and EE esophageal biopsies.
  • FIG. 6 shows fluticasone propionate treatment-resistant genes within the EE transcriptome.
  • Eotaxin-3 is a CC chemokine with selective activity on eosinophils.
  • eotaxin-3 recruits and directs eosinophils to sites in the body, such as the esophagus, via chemoattraction.
  • Additional chemokines have been identified in the genome that encode for CC chemokines with eosinophil-selective chemoattractant activity, and have been designated eotaxin-1 and eotaxin-2.
  • eotaxin-3 The activity of eotaxin-3 is mediated by the selective expression of an eotaxin receptor, CCR3, on eosinophils.
  • CCR3 is a promiscuous receptor; it interacts with multiple ligands including macrophage chemoattractant proteins (MCP)-2, -3, and -4, RANTES (regulated upon activation normal T-cell expressed and secreted), and HCC-2 (MIP-5, leukotactin).
  • MCP macrophage chemoattractant proteins
  • RANTES regulated upon activation normal T-cell expressed and secreted
  • HCC-2 HCC-2
  • Esophageal tissue obtained from patients previously diagnosed with EE was analyzed. Diagnosis was based on analysis of excised tissue from endoscopic biopsy. Tissues from patients with EE, as well as patients not having EE (controls) were subjected to genome-wide microarray transcript profiling (Affymetrix GeneChip). All work was performed at the Core facility at Children's Hospital Medical Center (Cincinnati Ohio).
  • RNA quality was first assessed using the Agilent bioanaiyzer (Agilent Technologies, Palo Alto Calif.). Only mRNA having a ratio of 28S/18S between 1.3 and 2 were subsequently used. RNA was converted to cDNA with Superscript choice for cDNA synthesis (Invitrogen, Carlsbad Calif.) and subsequently converted to biotinylated cRNA with Enzo High Yield RNA Transcript labeling kit (Enzo Diagnostics, Farmingdale N.Y.). After hybridization to the GeneChip (Affymetrix, Santa Clara Calif.), the chips were automatically washed and stained with streptavidin-phycoerythrin using a fluidics system. The chips were scanned with a Hewlett Packard GeneArray Scanner. Over 30,000 unique genes were screened.
  • Levels of gene transcripts were determined from data image files, using algorithms in the Microarray Analysis Suite software (Affymetrix). Levels from chip to chip were compared by global scaling. Each gene was typically represented by a probe set of 16 to 20 probe pairs. Each probe pair consisted of a perfect match oligonucleotide and a mismatch oligonucleotide that contained a one base mismatch at a central position. Two measures of gene expression were used, absolute call and average difference. Absolute call is a qualitative measure in which each gene is assigned a call of present, marginal or absent, based on the hybridization of the RNA to the probe set.
  • Average difference is a quantitative measure of the level of gene expression, calculated by taking the difference between mismatch and perfect match of every probe pair and averaging the differences over the entire probe set. Data were normalized and an EE transcriptome gene list was created with results having p ⁇ 0.01 (Welch t-test with or without false rate discovery) and ⁇ 1.5-fold change.
  • FIG. 1 shows the normalized relative average difference of the gene encoding eotaxin-3 from normal patients and patients with EE.
  • the microarray analysis identified eotaxin-3 as the top gene induced, indicating a role in EE. Eotaxin-1 and eotaxin-2 mRNA levels were not significantly increased in EE patients.
  • PCR Quantitative polymerase chain reaction
  • LightCycler technology Roche Diagnostics Corp. Indianapolis Ind.
  • eotaxin-3 mRNA was induced nearly 100-fold in patients with EE when normalized to a housekeeping gene GAPDH.
  • Patients with GERD showed only slightly increased levels compared to normal patients.
  • Levels of the other two eotaxin mRNA species were not increased in patient esophageal samples (data not shown), validating the specific role of eotaxin-3.
  • a murine model of EE was evaluated to determine the role of the eotaxin-3 receptor, CCR3.
  • the model is disclosed in Mishra et al., J. Clin. Invest . (2001) 107, 83, which is expressly incorporated by reference herein in its entirety.
  • EE is marked by infiltration of eosinophils, this condition may be linked to exposure to allergens.
  • animals models of EE were induced by allergen exposure to the respiratory tract.
  • mice were exposed to repeated doses of intranasal Aspergillus fumigatus antigen (three doses a week) for three weeks. Subsequently, the mice were euthanized 18 hours after the last dose of allergen or saline control, and the esophagus was analyzed for the occurrence of EE.
  • asthma was experimentally induced in wild-type and CCR3 knockout (KO) mice (a gift of Drs. Craig Gerard and Allison Humbles at Harvard Medical School) using Aspergillus fumigatus (ASP) as an allergen.
  • Wild-type control mice received saline.
  • the concentration of eosinophils was determined in the esophagus of allergen-induced wild-type mice (ASP wt), control wild-type mice (saline wt), and allergen-induced mice lacking the gene encoding CCR3 (ASP CCR3KO). The results are shown in FIG. 3 .
  • the concentration of eosinophils in allergen-induced wild-type mice was about 75 eosinophils per mm 2 .
  • the concentration of eosinophils in allergen-induced CCR3KO mice was about 4 eosinophils per mm 2 , similar to the eosinophil concentration in control wild-type mice (saline wt).
  • EE-related symptoms and/or pathology may be mitigated by mediating eosinophil chemotactic events using techniques such as those disclosed in U.S. Pat. No. 6,780,973, which is expressly incorporated by reference herein in its entirety.
  • One example is a recombinant polypeptide capable of mediating eosinophil chemotactic events where the polypeptide includes a domain having a sequence which has at least 70% identity to full length murine eotaxin cDNA, full length guinea pig eotaxin cDNA, and/or human eotaxin DNA.
  • Another example is reducing eotaxin activity using an antagonist such as an antieotaxin-3 antibody or eotaxin-1, -2, or -3 fragment, a purified antibody which binds specifically to a murine or human eotaxin-3 protein indicating an intact monoclonal or polyclonal antibody, an immunologically active antibody fragment, or a genetically engineered fragment.
  • the antagonist may be an eotaxin-1, -2, or -3 polypeptide having a deletion of 1-10 N-terminal amino acids, or having an addition of 3-10 amino acids on the amino terminus.
  • EDTA ethylenediamine tetraacetic acid
  • a plasma concentration of eotaxin-3 of about 52.97 pg/ml ⁇ 12 pg/ml in blood anticoagulated with heparin is indicative of EE.
  • a plasma concentration of eotaxin-3 of about 18.19 pg/ml ⁇ 7 pg/ml in blood anticoagulated with EDTA is indicative of EE.
  • These blood concentrations of eotaxin-3 may serve as a diagnostic marker, for which a less invasive diagnostic test for EE may be used, as further discussed below, to replace or serve as a preliminary indicator or whether a more invasive test, e.g. endoscopic biopsy, is warranted.
  • the level of eotaxin-3 may also serve to determine if a specific therapy is mitigating EE, and thus may be used to monitor therapy.
  • concentration or amount of eotaxin-3 DNA, eotaxin-3 mRNA, or eotaxin-3 protein over a normal amount in a patient tissue, such as blood or esophageal tissue, can be utilized further as an indicator of EE in the patient.
  • biopsy tissues obtained from the distal esophagus during routine endoscopy were submerged in formalin for routine pathological analysis with hematoxylin and eosin staining. Diagnosis was established based on the maximum eosinophil count per high power field (hpf) and basal layer expansion according to method known in the art (e.g., established criteria in Rothenberg et al., Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy Clin Immunol 108 (2001) 891; Attwood et al., Esophageal eosinophilia with dysphagia.
  • hpf maximum eosinophil count per high power field
  • 1620 genes were expressed significantly differently in EE patients compared to normal individuals, meaning that, at p ⁇ 0.01, these 1620 genes from EE patients, using a patient pool size of 89, of which 76 patients had been diagnosed with EE, and 13 patients were individuals without EE, were either up-regulated or down-regulated by ⁇ 1.5 fold, compared to normal individuals (NL).
  • the data were analyzed by cluster analysis and ordered (standard correlation (A) and distance (B)) using Genespring software. Results are shown in FIG. 5 and Table 1.
  • A standard correlation
  • B distance
  • Results are shown in FIG. 5 and Table 1.
  • down-regulated genes were depicted in blue; and up-regulated genes were depicted in red, with the magnitude of the gene change proportional to the intensity of the blue and/or red colors.
  • Each column represented a separate individual and each line a gene.
  • RNA from each patient was subjected to chip analysis using Affymetrix Human Genome U133 GeneChip plus 2.
  • SEQ_ID_#52 Transcribed locus 5.183 BQ004901 52 CHL1 Cell adhesion molecule with homology to 5.1 NM_006614 53 L1CAM (close homolog of L1) C9orf150 Chromosome 9 open reading frame 150 4.944 NM_203403 54 APOL1 Apolipoprotein L, 1 4.935 NM_003661 55 SEQ_ID_#56 LOC441801 4.841 BC037919 56 CH25H Cholesterol 25-hydroxylase 4.828 NM_003956 57 SEQ_ID_#58 4.822 XM_294092 58 SIDT1 Hypothetical protein FLJ21394 4.822 NM_017699 59 SLC28A3 Solute carrier family 28 (sodium-coupled 4.775 NM_022127 60 nucleoside transporter), member 3 UPK1B Uroplakin 1B 4.732 NM_006952 61 IL13RA2 Interleukin 13 receptor, alpha 2
  • PRRX1 Paired related homeobox 1 4.375 NM_006902 71 SEQ_ID_#72 Transcribed locus 4.374 AW978130 72 SERPINB4 Serine (or cysteine) proteinase inhibitor, 4.328 NM_002974 73 clade B (ovalbumin), member 4 RGS13 Regulator of G-protein signalling 13 4.306 NM_002927 74 SLC16A1 AKR7 family pseudogene 4.285 NM_003051 75 LOC340061 Hypothetical protein LOC340061 4.211 NM_198282 76 TIMP1 Tissue inhibitor of metalloproteinase 1 4.158 NM_003254 77 (erythroid potentiating activity, collagenase inhibitor) SFRP1 Secreted frizzled-related protein 1 4.098 NM_003012 78 GCNT3 Glucosaminyl (N-acetyl) transferase 3, 4.078 NM_004751
  • ATF3 isoform 3 is encoded by transcript variant 2.844 NM_001030287 149 3; ATF3deltaZip3; ATF3deltaZip2c; go_component: nucleus [goid 0005634] [evidence IEA]; go_function: DNA binding [goid 0003677] [evidence IEA]; go_function: transcription factor activity [goid 00037
  • SLC15A1 Solute carrier family 15 (oligopeptide 2.792 NM_005073 151 transporter), member 1 AIM2 Absent in melanoma 2 2.788 NM_004833 152 KIT V-kit Hardy-Zuckerman 4 feline sarcoma 2.776 NM_000222 153 viral oncogene homolog IL15 Interleukin 15 2.772 NM_000585 154 RASGRP1 RAS guanyl releasing protein 1 (calcium 2.769 NM_005739 155 and DAG-regulated) SLC27A2 Solute carrier family 27 (fatty acid 2.766 NM_003645 156 transporter), member 2 IFIT3 Interferon-induced protein with 2.763 NM_001549 157 tetratricopeptide repeats 3 LRRC8D Leucine rich repeat containing 8 family, 2.761 NM_018103
  • SEQ_ID_#186 Transcribed locus 2.617 BF025845 186 TSPAN3 Tetraspanin 3 2.614 NM_005724 187 ADAM28 A disintegrin and metalloproteinase 2.613 NM_014265 188 domain 28 SEPX1 Selenoprotein X, 1 2.611 NM_016332 189 IL27RA Interleukin 27 receptor, alpha 2.606 NM_004843 190 NAV1 Neuron navigator 1 2.603 NM_020443 191 MET Met proto-oncogene (hepatocyte growth 2.592 NM_000245 192 factor receptor) SEQ_ID_#193 cs100c01.y1 Human Retinal pigment 2.591 CA389545 193 epithelium/choroid cDNA (Un-normalized, unamplified): cs Homo sapiens cDNA clone cs100c01 5′, mRNA sequence.
  • SOCS3 Suppressor of cytokine signaling 3 2.589 NM_003955 194 ID3 Inhibitor of DNA binding 3, dominant 2.584 NM_002167 195 negative helix-loop-helix protein BID BH3 interacting domain death agonist 2.582 NM_001196 196 THEDC1 Thioesterase domain containing 1 2.568 NM_018324 197 LR8 LR8 protein 2.564 NM_014020 198 CEL Carboxyl ester lipase (bile salt-stimulated 2.557 NM_001807 199 lipase) CALML4 2.555 NM_001031733 200 LOC387882 LOC387882 hypothetical protein 2.551 NM_207376 201 NEK6 NIMA (never in mitosis gene a)-related 2.513 NM_014397 202 kinase 6 NCF1 Neutrophil cytosolic factor 1 (47 kDa, 2.509 NM_000265 203 chronic gran
  • SOCS1 Suppressor of cytokine signaling 1 2.306 NM_003745 244 SEQ_ID_#245 oc22e04.s1 NCI_CGAP_GCB1 Homo 2.303 AA806368 245 sapiens cDNA clone IMAGE: 1350462 3′ similar to contains Alu repetitive element; contains element PTR5 repetitive element;, mRNA sequence.
  • CD52 CD52 antigen (CAMPATH-1 antigen) 2.184 NM_001803 275 ADA Adenosine deaminase 2.183 NM_000022 276 CXCL16 Chemokine (C—X—C motif) ligand 16 2.179 NM_022059 277 IFIH1 Interferon induced with helicase C domain 1 2.174 NM_022168 278 ZSWIM5 Zinc finger, SWIM-type containing 5 2.169 XM_046581 279 VMP1 Transmembrane protein 49 2.168 NM_030938 280 UBE2L6 Ubiquitin-conjugating enzyme E2L 6 2.164 NM_004223 281 ARHGAP8; PRR5; Rho GTPase activating protein 8 2.164 NM_017701 282 PP610; BPGAP1; FLJ20185 IRF1 Interferon regulatory factor 1 2.161 NM_002198 283 C1orf188 Hypothetical protein FLJ32096
  • CAPN14 Calpain 14 2.067 AK092257 320 ELOVL5 ELOVL family member 5, elongation of 2.065 NM_021814 321 long chain fatty acids (FEN1/Elo2, SUR4/Elo3-like, yeast) GPR143
  • G protein-coupled receptor 143 2.06 NM_000273 322
  • FLJ14466 Hypothetical protein FLJ14466 2.045 NM_032790 324 LOC285016; synonyms: PRO1097, RGPG542; Homo 2.045 XM_211736 325 PRO1097; RGPG542 sapiens hypothetical protein LOC285016 (LOC285016), mRNA.
  • NFATC2 Nuclear factor of activated T-cells, 1.949 NM_173091 368 cytoplasmic, calcineurin-dependent 2 SLC9A3 Solute carrier family 9 (sodium/hydrogen 1.948 AL137723 369 exchanger), isoform 3 SEQ_ID_#370 CDNA: FLJ23006 fis, clone LNG00414 1.948 AK026659 370 C6orf173 Chromosome 6 open reading frame 173 1.946 NM_001012507 371 CYP4X1 Cytochrome P450, family 4, subfamily X, 1.946 NM_178033 372 polypeptide 1 DUSP10 Dual specificity phosphatase 10 1.945 NM_007207 373 PTPN6 Protein tyrosine phosphatase, non- 1.943 NM_002831 374 receptor type 6 FGF11 Fibroblast growth factor 11 1.94 NM_004112 375 NFIL3
  • ELF4 E74-like factor 4 (ets domain 1.92 NM_001421 389 transcription factor) ARHGEF5 Rho guanine nucleotide exchange factor 1.919 NM_001002861 390 (GEF) 5 PRODH Proline dehydrogenase (oxidase) 1 1.913 NM_016335 391 GALNAC4S-6ST B cell RAG associated protein 1.913 NM_015892 392 MGC17791 Tumor necrosis factor, alpha-induced 1.912 NM_152362 393 protein 8-like 1 BIK BCL2-interacting killer (apoptosis- 1.911 NM_001197 394 inducing) FAM54A Family with sequence similarity 54, 1.911 NM_138419 395 member A VWA1 Von Willebrand factor A domain 1.91 NM_022834 396 containing 1 LOC401115 Hypothetical gene supported by 1.909 XM_379250 397 BC038466; BC062790 CD40
  • DOK3 Docking protein 3 1.79 NM_024872 492 DNAPTP6 DNA polymerase-transactivated protein 6 1.787 NM_015535 493 LOC285835 Hypothetical protein LOC285835 1.787 BC035656 494 CDC20 CDC20 cell division cycle 20 homolog ( S. cerevisiae ) 1.781 NM_001255 495 SEQ_ID_#496 AGENCOURT_7258511 NIH_MGC_71 1.781 BQ219651 496 Homo sapiens cDNA clone IMAGE: 5786579 5′, mRNA sequence.
  • TNFRSF10A Tumor necrosis factor receptor 1.78 NM_003844 497 superfamily, member 10a KIF4A Kinesin family member 4A 1.779 NM_012310 498 SEQ_ID_#499 UI-CF-FN0-afk-f-10-0-UI.s1 UI-CF-FN0 1.777 CA312567 499 Homo sapiens cDNA clone UI-CF-FN0-afk- f-10-0-UI 3′, mRNA sequence.
  • ROBO1 Roundabout, axon guidance receptor, 1.666 NM_002941 607 homolog 1 ( Drosophila ) ADAM12 A disintegrin and metalloproteinase 1.665 NM_003474 608 domain 12 (meltrin alpha) BDNF Brain-derived neurotrophic factor 1.664 NM_001709 609 opposite strand RPS8 Ribosomal protein S8 1.663 NM_001012 610 P2RY2 Purinergic receptor P2Y, G-protein 1.661 NM_002564 611 coupled, 2 C9orf55 Chromosome 9 open reading frame 55 1.661 NM_017925 612 IKBKE Inhibitor of kappa light polypeptide gene 1.661 NM_014002 613 enhancer in B-cells, kinase epsilon RARA Retinoic acid receptor, alpha 1.661 NM_000964 614 ST6GALNAC2 ST6 (alpha-N-
  • KCTD7 Potassium channel tetramerisation 1.529 NM_153033 784 domain containing 7 RANGNRF RAN guanine nucleotide release factor 1.528 NM_016492 785 KIAA1505 KIAA1505 protein 1.528 NM_020879 786 SEQ_ID_#787 UI-H-BI4-apu-h-06-0-UI.s1 1.528 BF512055 787 NCI_CGAP_Sub8 Homo sapiens cDNA clone IMAGE: 3088762 3′, mRNA sequence.
  • MARVELD3 MARVEL domain containing 3 1.528 NM_052858 788 MYOC Myocilin, trabecular meshwork inducible 1.528 BM712946 789 glucocorticoid response CCND3 Cyclin D3 1.526 NM_001760 790 NAT1 N-acetyltransferase 1 (arylamine N- 1.524 NM_000662 791 acetyltransferase) CD97 CD97 antigen 1.524 NM_001025160 792 OCIAD2 OCIA domain containing 2 1.522 NM_001014446 793 PKIA Protein kinase (cAMP-dependent, 1.522 NM_006823 794 catalytic) inhibitor alpha C2 Complement component 2 1.521 NM_000063 795 ACD Adrenocortical dysplasia homolog 1.521 NM_022914 796 (mouse) FAM83E Hypothetical protein FLJ20200 1.521 NM_017708 797 S100
  • pombe 1.517 NM_001274 803 ZNF326 Zinc finger protein 326 1.516 NM_181781 804 HDHD1A Haloacid dehalogenase-like hydrolase 1.515 NM_012080 805 domain containing 1A SEQ_ID_#806 CDNA FLJ31593 fis, clone NT2RI2002481 1.514 AK056155 806 SEQ_ID_#807 UI-H-CO0-asu-e-10-0-UI.s1 1.514 BM988141 807 NCI_CGAP_Sub9 Homo sapiens cDNA clone IMAGE: 5859954 3′, mRNA sequence.
  • SEQ_ID_#808 Transcribed locus 1.513 BM994952 808 WARP Von Willebrand factor A domain 1.513 NM_022834 809 containing 1 FLJ22794 FLJ22794 protein 1.513 NM_022074 810 STAT2 Signal transducer and activator of 1.512 NM_005419 811 transcription 2, 113 kDa SEQ_ID_#812 Homo sapiens , clone IMAGE: 5092955 1.512 BC046188 812 ANKRD10 Ankyrin repeat domain 10 1.512 NM_017664 813 SLC25A29 Solute carrier family 25, member 29 1.511 NM_152333 814 SSBP2 Single-stranded DNA binding protein 2 1.51 BQ027821 815 BCL11B B-cell CLL/lymphoma 11B (zinc finger 1.509 NM_022898 816 protein) ADAR Adenosine deaminase, RNA-specific 1.509 NM_001025107 817
  • MFSD1 Major facilitator superfamily domain 0.638 NM_022736 911 containing 1 CPEB2 Cytoplasmic polyadenylation element 0.638 NM_182485 912 binding protein 2 FOSL2 FOS-like antigen 2 0.638 NM_005253 913 NFIB Nuclear factor I/B 0.638 NM_005596 914 SEQ_ID_#915 602068385F1 NIH_MGC_58 Homo 0.638 BF542107 915 sapiens cDNA clone IMAGE: 4067421 5′, mRNA sequence.
  • ANKRD15 Ankyrin repeat domain 15 0.632 NM_015158 931 KA36 Type I hair keratin KA36 0.632 NM_182497 932 CKAP4 Cytoskeleton-associated protein 4 0.632 NM_006825 933 13CDNA73 Hypothetical protein CG003 0.632 NM_023037 934 EPS15L1 Epidermal growth factor receptor pathway 0.632 NM_021235 935 substrate 15-like 1 CYP2C9 Cytochrome P450, family 2, subfamily C, 0.632 NM_000771 936 polypeptide 9 ADAMTS17 A disintegrin-like and metalloprotease 0.631 AK057529 937 (reprolysin type) with thrombospondin type 1 motif, 17 SCEL Sciellin 0.631 NM_003843 938 PDK1 Pyruvate dehydrogenase kinase, 0.631 NM_002610 939 isoenzyme 1
  • GALNT12 UDP-N-acetyl-alpha-D- 0.586 NM_024642 1076 galactosamine:polypeptide N- acetylgalactosaminyltransferase 12 (GalNAc-T12) CHP Calcium binding protein P22 0.586 NM_007236 1077 SESN2 Sestrin 2 0.586 NM_031459 1078 MGC9913 Hypothetical protein MGC9913 0.585 XM_378178 1079 HTR3B 5-hydroxytryptamine (serotonin) receptor 0.585 NM_006028 1080 3B ACOT11 Thioesterase, adipose associated 0.585 NM_147161 1081 LOC221362 Hypothetical protein LOC221362 0.584 AK091117 1082 SEC14L1 SEC14-like 1 ( S.
  • FAM62B Family with sequence similarity 62 (C2 0.577 NM_020728 1104 domain containing) member B ANKH Ankylosis, progressive homolog (mouse) 0.577 NM_054027 1105 SEQ_ID_#1106 0.576 XM_379938 1106 SLC13A4 Solute carrier family 13 (sodium/sulfate 0.576 NM_012450 1107 symporters), member 4 CDS1 CDP-diacylglycerol synthase 0.576 NM_001263 1108 (phosphatidate cytidylyltransferase) 1 KDELR3 KDEL (Lys-Asp-Glu-Leu) endoplasmic 0.576 NM_006855 1109 reticulum protein retention receptor 3 HIPK2 synonym: PRO0593; homeodomain- 0.575 NM_014075 1110 interacting protein kinase 2; go_component: cytoplasm [
  • PBEF1 Pre-B-cell colony enhancing factor 1 0.575 NM_005746 1111 ZNF117 Zinc finger protein 117 (HPF9) 0.574 NM_015852 1112 CFTR Cystic fibrosis transmembrane 0.574 NM_000492 1113 conductance regulator, ATP-binding cassette (sub-family C, member 7) PER3 Period homolog 3 ( Drosophila ) 0.573 NM_016831 1114 KRTHA3A Keratin, hair, acidic, 3A 0.573 NM_004138 1115 SGEF Src homology 3 domain-containing 0.573 NM_015595 1116 guanine nucleotide exchange factor ENSA Endosulfine alpha 0.572 NM_207043 1117 WNK4 WNK lysine deficient protein kinase 4 0.572 NM_032387 1118 SLC2A13 Solute carrier family 2 (facilitated glucose 0.572 NM_052885 1119
  • B3GNT5 UDP-GlcNAc betaGal beta-1,3-N- 0.559 NM_032047 1161 acetylglucosaminyltransferase 5 SCGB2A1 Secretoglobin, family 2A, member 1 0.558 NM_002407 1162 ZNF416 Zinc finger protein 416 0.558 NM_017879 1163 LOC146174 Chromosome 16 open reading frame 52 0.557 NM_173501 1164 TPM4 Tropomyosin 4 0.556 NM_003290 1165 KRTHA2 Keratin, hair, acidic, 2 0.556 NM_002278 1166 CPVL Carboxypeptidase, vitellogenic-like 0.555 NM_019029 1167 GADD45B Growth arrest and DNA-damage- 0.555 NM_015675 1168 inducible, beta SEQ_ID_#1169 BX109361 NCI_CGAP_Lu5 Homo sapiens 0.554
  • SLC5A1 Solute carrier family 5 (sodium/glucose 0.554 NM_000343 1170 cotransporter), member 1 HNMT Histamine N-methyltransferase 0.554 NM_001024074 1171 SEQ_ID_#1172 CDNA FLJ31407 fis, clone NT2NE2000137 0.554 AK055969 1172 SNX24 Sorting nexing 24 0.554 NM_014035 1173 CPD Carboxypeptidase D 0.553 NM_001304 1174 SEQ_ID_#1175 Transcribed locus 0.553 BX116062 1175 LOC162993 Hypothetical protein LOC162993 0.553 XM_091914 1176 CUL4B Cullin 4B 0.552 NM_003588 1177 H41 Hypothetical protein H41 0.551 NM_017548 1178 SEQ_ID_#1179 CDNA clone IMAGE: 4830452 0.551
  • SFT2D2 SFT2 domain containing 2 0.536 NM_199344 1210 DEGS2 Degenerative spermatocyte homolog 2, 0.536 BE512716 1211 lipid desaturase ( Drosophila ) ERO1L ERO1-like ( S.
  • elegans 0.512 NM_022051 1267 PHTF2 Putative homeodomain transcription 0.511 NM_020432 1268 factor 2 GP1BB Glycoprotein Ib (platelet), beta 0.511 NM_000407 1269 polypeptide BCAR3 Breast cancer anti-estrogen resistance 3 0.51 NM_003567 1270 LNX2 Ligand of numb-protein X 2 0.508 NM_153371 1271 RPL23AP7; Homo sapiens cDNA FLJ30702 fis, clone 0.507 AK055264 1272 RPL23AL1; FCBBF2001001.
  • ZDHHC20 Zinc finger DHHC-type containing 20 0.283 NM_153251 1555 LOC115749 Hypothetical protein LOC115749 0.281 XM_056680 1556 NGEF Neuronal guanine nucleotide exchange 0.279 NM_019850 1557 factor LOC56901 NADH:ubiquinone oxidoreductase MLRQ 0.278 NM_020142 1558 subunit homolog SORBS1 0.277 NM_001034954 1559 HCG22 HLA complex group 22 0.276 XM_496804 1560 FLJ40432 Hypothetical protein FLJ40432 0.275 NM_152523 1561 SBSN Suprabasin 0.274 NM_198538 1562 TNFAIP3 Tumor necrosis factor, alpha-induced 0.273 BG218400 1563 protein 3 ZNF101 Zinc finger protein 101 0.27 NM_033204 1564 ZBED2 Zinc finger, BED-type containing 2
  • FNDC4 Fibronectin type III domain containing 4 0.259 NM_022823 1570 PAQR8 Progestin and adipoQ receptor family 0.255 NM_133367 1571 member VIII SEQ_ID_#1572 Similar to ankyrin repeat domain 20A 0.248 AK092114 1572 IL8RB Interleukin 8 receptor, beta 0.244 NM_001557 1573 HIST1H2BC Histone 1, H2bc 0.243 NM_003526 1574 RGS17 Regulator of G-protein signalling 17 0.243 NM_012419 1575 SLURP1 Secreted LY6/PLAUR domain containing 1 0.24 NM_020427 1576 BBOX1 Butyrobetaine (gamma), 2-oxoglutarate 0.238 NM_003986 1577 dioxygenase (gamma-butyrobetaine hydroxylase) 1 EDN3 Endothelin 3 0.229 NM_000114 1578 MT1G Metall
  • EE transcript signature also termed an EE transcriptome.
  • the most induced transcript in EE was eotaxin-3; levels of eotaxin-3 strongly correlated with disease severity.
  • the EE transcriptome was used to evaluate EE patients pre- and post-treatment regimens.
  • corticosteroids are frequently administered to patients with EE, and the specific glucocorticoid fluticasone propionate has been shown to induce EE disease remission (Gastroenterology 131 (2006) 1381) and to reverse EE gene dysregulation (J. Allergy Clin. Immunol., 120 (2007) 1292; U.S. Application Ser. No. 61/118,981, filed Dec. 1, 2008), each of which is incorporated by reference herein in its entirety.
  • these 13 genes can be used to evaluate a patient's propensity to EE, particularly in the absence of clinical or physical symptoms of EE or microscopic findings typical of EE. Because the profiles of these genes, i.e., whether they were over-expressed or under-expressed, did not change when the patient was on therapy, these 13 genes can be used to evaluate whether a patient had EE in the past or currently has inactive EE. These 13 genes can be used to evaluate EE in an asymptomatic population or when past EE is suspected in a non-active EE individual at the time of endoscopy.
  • the expression level of at least one of these 13 genes is compared to control levels and under- or over-expression of one or more of these 13 genes by ⁇ 1.5 fold, indicating that the patient is either a past EE patient and/or is susceptible to future EE disease development.
  • the method may evaluate treatment efficacy with different drugs within a particular group (e.g., different corticosteroids), among the same group (e.g., corticosteroids compared to non-corticosteroids), or among different groups (e.g., steroids compared to non-steroid drugs).
  • the method may evaluate treatment efficacy at different doses, provided in different therapeutic regimens (e.g., frequency, duration, etc.).
  • EE transcriptome Normalization of expression levels of 99% of the genes in the EE transcriptome by fluticasone propionate treatment permitted determination of potential pathways by which fluticasone propionate and other treatments, e.g., other glucocorticoids, treat EE.
  • the EE transcriptome was used to examine the cellular and molecular pathways of EE, and the way by which a particular therapy treated EE, provided information about the basis, attributes, and potential modifiers of EE. For example, a role of interleukin 13 (IL-13) and its signaling pathways has been implicated in the pathophysiology of EE, as described in U.S. Application Ser. No. 61/118,981, filed Dec. 1, 2008, which is incorporated by reference herein in its entirety.
  • IL-13 interleukin 13
  • the 1620 genes in the EE transcriptome are highly conserved. Their complex expression pattern delineates molecular features, cell composition, and cell activation in EE.
  • the EE transcriptome was compared to transcriptomes in cell/tissues that had been treated with one or more compounds potentially involved with and/or efficacious against EE.
  • the EE transcriptome was compared to transcriptome of, e.g., a simple in vitro or ex vivo model of a particular compound, one can assess the percentage of genes that are dysregulated in EE due to that particular compound.
  • a compound was used to stimulate an esophageal cell type.
  • the genes that were dysregulated in this model, and hence exhibit an altered transcriptome allowed one to determine the percentage of genes that were dysregulated in EE due to treatment with this compound.
  • a transcriptome generated in esophageal epithelial cells that had been stimulated with IL-13 revealed that 20% of the genes of the EE transcriptome were potentially due to IL-13 stimulation of esophageal epithelial cells.
  • evaluation of the EE transcriptome was used to determine efficacy of non-drug therapies. For example, having patients with EE follow a controlled diet, where some foodstuffs are limited or eliminated, normalized expression levels of many genes in the EE transcriptome, as shown in FIG. 6 . Elimination diets that completely eliminate certain foodstuffs (e.g., wheat, soy, milk, peanuts, and/or seafood) and elemental diets that completely lack certain elements (e.g., liquid diets that contain only amino acids but no proteins to act as allergens) have been used with some success to treat children with EE.
  • the EE transcriptome is used to assess potential non-drug EE treatments by comparing the gene expression profile pre- and post-such treatment. For example, a child with EE may be put on an elimination diet for a defined period, and the gene expression profile compared before, during, and at the termination of the defined period to assess effect of the foodstuff that was eliminated from the child's diet during the period.
  • Some individuals with EE do not respond to treatment ( FIG. 5 ). Even after they have received treatment (e.g., a particular drug, elimination diet, elemental diet, etc.), such non-responder individuals have an EE transcriptome that resembles untreated EE patients, i.e., genes that are up-regulated in EE and genes that are down-regulation in EE remain up-regulated and down-regulated, respectively, despite the individual having received a particular treatment for EE.
  • treatment e.g., a particular drug, elimination diet, elemental diet, etc.
  • Analysis of the gene expression profile pre- and post-treatment allows a medical practitioner to determine whether a particular treatment method demonstrates efficacy, or whether an alternative form of treatment, or a different treatment regime (e.g., increased dosing) is warranted.
  • analysis of the EE transcriptome is used to assess whether a patient is responding to a particular treatment.
  • analysis of the EE transcriptome is used to assess and/or monitor patient compliance. For example, a patient with EE may not respond to therapy because the patient is a non-responder, or may not respond to therapy because the patient is not complying with the complete dosage regimen and thus may have a subthreshold drug concentration.
  • evaluation of the EE transcriptome was used to assess EE in the presence of another pathology that may confound the diagnosis of EE. While EE is commonly diagnosed using histological methods to assess the level of eosinophil infiltration into, and/or thickening of, esophageal tissue, the presence and extent of eosinophil infiltration can be affected by various factors. The esophagus is normally devoid of eosinophils.
  • eosinophils can infiltrate the esophagus in pathological condition such as parasitic infection, fungal infections, hypereosinophilic syndromes, inflammatory bowel disease, certain cancers, recurrent vomiting, gastroesophageal reflux disease (GERD), etc., in addition to EE, so eosinophil presence/concentration in the esophagus cannot definitively diagnose between, e.g., EE and GERD. These diseases need to be ruled out before EE can be diagnosed. Evaluation of the EE transcriptome to identify the genes specifically involved in EE, e.g., eotaxin-3, allows one to discriminate between these pathologies and rule in or rule out EE with enhanced definiteness.
  • pathological condition such as parasitic infection, fungal infections, hypereosinophilic syndromes, inflammatory bowel disease, certain cancers, recurrent vomiting, gastroesophageal reflux disease (GERD), etc.
  • EE The diagnosis of EE is often suspected whenever dysphagia for solid food occurs, although it is not one of the more common causes of dysphagia.
  • Dysphagia is frequently evaluated with endoscopy (esophagogastroduodenoscopy, or EGD) to determine its cause.
  • EGD esophagogastroduodenoscopy
  • a flexible viewing tube or endoscope is inserted through the mouth and into the esophagus, permitting the medical practitioner to see the inner esophageal mucosa and lumen.
  • Certain abnormalities such as narrowing of most of the esophagus, or a series of rings along the entire length of the esophagus, suggest EE.
  • the esophagus appears normal or shows only minor abnormalities.
  • an accurate diagnosis of EE using visual and/or histological methods depends on the presence of characteristics that may or may not be present.
  • the accurate diagnosis of EE using histological evaluation of a tissue biopsy specimen depends on when the biopsy is obtained. For example, histological evaluation may differ in early-stage EE biopsy tissue compared to later-stage biopsy EE tissue.
  • the accurate diagnosis of EE may be compromised if other pathologies are present.
  • Evaluation of the EE transcriptome permitted a more accurate assessment, diagnosis, determination of course, etc., of EE.
  • Evaluation of the EE transcriptome may be performed independent of, or concomitant with, other assessment methods such as, e.g., histological evaluation of a tissue biopsy specimen. Evaluation of the EE transcriptome may be performed, e.g., when eosinophil infiltration has not reached pre-determined numbers, in disease remission, in the absence of physical characteristics, or in the presence of one or more confounding pathologies.
  • evaluation of the EE transcriptome is used to diagnose past, present, and/or future EE disease.
  • the pathologist based upon the microscopic appearance, typically reports the patient as normal with no diagnosis abnormality.
  • evaluation of the EE transcriptome reveals dysregulation of the 13 non-responsive genes despite the normal histological appearance of biopsy tissues.
  • eosinophil tissue infiltration is a marker of active EE
  • evaluation of the EE transcriptome provides information of EE history, e.g., it can assess presence and/or severity of prior pathology. Such assessment is useful because the dynamic and seasonal nature of EE is known.
  • evaluation of the EE transcriptome is used to diagnose EE in the absence of overt disease, i.e., EE variability and/or inherency.
  • the expression level of the 13 non-responsive genes is used to diagnose EE in the absence of overt or active disease.
  • the 13 non-responsive genes allow diagnosis of chronic and relapsing forms of EE, and may provide an understanding of the pathophysiology of these forms.
  • evaluation of the EE transcriptome can identify sporadic, e.g. recurring or relapsing, forms of EE. As described above, histological assessment of a tissue biopsy specimen and extent of tissue eosinophil infiltration depends on when, during the course of EE, the assessment is performed. In contrast, a sporadic form of EE that is missed by these methods would, in fact, be captured by evaluating the EE transcriptome because the under-expression or over-expression exhibited by these genes is independent of active EE.
  • evaluation of the EE transcriptome is used to assess familial components or contributions to EE by providing a transcriptome basis of comparison among genetic family members of the EE patient. There is evidence indicating a strong familial association or aggregation for EE. Approximately 10% of parents of EE patients have a history of esophageal strictures, and approximately 8% of these have EE as established by histological evaluation of a tissue biopsy specimen.
  • ⁇ S sibling recurrence risk ratio
  • a value for ⁇ S>1 indicates an increased risk of EE development among siblings of the proband, compared to the general population.
  • the prevalence of EE in the general population is approximately 5/10,000.
  • the estimated sibling recurrence risk ratio, ⁇ S, for EE is approximately 80.
  • ⁇ S is estimated at approximately 2
  • evaluation of the EE transcriptome is used to identify candidate genes responsible for a familiar association.
  • the gene for eotaxin-3 gene was one candidate gene.
  • a single nucleotide polymorphism (SNP), +2496 T>G, rs2302009) in the gene for eotaxin-3 showed association with EE by both population-based case-control comparison and family-based transmission disequilibrium testing.
  • SNP single nucleotide polymorphism
  • the evaluation of the EE transcriptome among genetic family members, some of who exhibited symptoms of EE may provide early EE diagnosis in other family members who did not exhibit symptoms. Such information facilitates determination of hereditary factors for EE.
  • a diagnostic assay for eosinophilic esophagitis includes an ELISA (enzyme linked immunosorbent assay) or other clinically applicable immunoassay.
  • a diagnostic assay for eosinophilic esophagitis includes a test strip containing an anti-eotaxin-3 binding substance such as an antibody to which eotaxin-3 or eotaxin-3 like protein or peptide in a patient's biological sample (e.g. blood, sputum, feces, tissue fluid, cerebrospinal fluid, etc.) would bind.
  • the test strip may include a chromogenic, fluorogenic, or luminescent substrate, detection reagents, etc., as known to one skilled in the art.
  • the anti-eotaxin-3 antibody may be a rodent or other animal antieotaxin-3 antibody.
  • the assay would include at least one suitable reagent, such as an enzyme (e.g. an oxidoreductase, transferase, hydrolase, lyase, isomerase, or ligase), in one embodiment horseradish peroxidase, o-toluidine, or colloidal gold, whereby the reagent reacts with an antigen/antibody complex on the test strip.
  • an enzyme e.g. an oxidoreductase, transferase, hydrolase, lyase, isomerase, or ligase
  • horseradish peroxidase o-toluidine
  • colloidal gold colloidal gold
  • a chromogen or other detectable indicator of binding or lack of binding indicates binding of the anti-eotaxin-3 antibody to eotaxin-3 present in a supranormal level for a qualitative test, and may indicate the degree of binding for a quantitative or semi-quantitative test. Binding typically is indicated or visually detected via the presence or absence of color, fluorescence, luminescence, etc.
  • assay format e.g. competitive, non-competitive, sandwich, etc.
  • suitable substrates and a suitable reagent may include, respectively, dimethyl or diethyl analogues of p-phenylenediamine with 4-chloro-1-naphthol or 3-methyl-2-benzothiazoline hydrazone with 4-chloro-1-naphthol and horseradish peroxidase.
  • Other exemplary substrates used with horseradish peroxidase include 3,3′,5,5′-tetramethylbenzidine, 2,2′-azinobis[3-ethylbenzothiazoline-6-sulfonic acid]-diammonium salt, o-phenylenediamine dihydrochloride, and QuantaBlu.
  • the anti-eotaxin-3 antibody may be a monoclonal or polyclonal antibody. Methods of producing monoclonal and polyclonal antibodies are known to one skilled in the art. Anti-eotaxin-3 antibodies may be generated as disclosed in U.S. Pat. No. 6,780,973, previously expressly incorporated by reference herein in its entirety. Also, a commercially available anti-eotaxin-3 antibody may be used. As indicated above, eotaxin-3 selectively signals through the CCR3 receptor expressed on activated eosinophils or on other cells such as mast cells.
  • eosinophilic esophagitis may be mitigated by altering an eotaxin-3 binding and/or signaling mechanism, and/or CCR3 structure, function, and/or internalization.
  • One such example is a method to provide an inhibitor to eotaxin-3 and/or CCR3 in an eosinophil or a mast cell under conditions sufficient to inhibit eotaxin-3 binding to the receptor.
  • the inhibitor may be provided to the esophageal tissue or to the blood stream in an amount sufficient to inhibit eotaxin-3 binding to the eotaxin-3 receptor.
  • the inhibitor may be a small molecule inhibitor and/or a CCR3 antagonist.
  • Exemplary CCR3 antagonists may include a humanized or human antieotaxin-3 antibody, MIG, I-TAO, IP-10 (U.S. patent application Ser. No. 10/752,659, titled “Cytokine Inhibition of Eosinophils,” filed on Jan. 1, 2004; Zimmermann et al., J. Allergy Clin. Immunol ., (2003) 3, 227), vMIP-II (Kleidel et al., Science , (1997) 277, 1656), met-RANTES (Elsner et al., Eur. J. Immunol ., (1997) 27, 2892), carboxamide derivatives (Naya et al., Bioorg. Med. Chem.
  • the inhibitor need not completely inhibit binding, signal transduction, and/or function or cause receptor internalization.
  • an inhibitor may cause any reduction in one or more of these properties compared to a normal level.
  • An eotaxin-3 and/or CCR3 inhibitor may also specifically inhibit transcription and/or translation of eotaxin-3, and/or CCR3 such as by utilizing antisense oligonucleotides and transcription factor inhibitors.
  • An inhibitor may include a glucocorticoid that can work by inhibiting eotaxin-3 promoter-driven reporter gene activity and accelerating the decay of eotaxin-3 mRNA (Zimmermann et al., J. Allergy Clin. Immunol., (2003) 3, 227).
  • An inhibitor may also induce CCR3 internalization (Zimmermann et al., J. Biol. Chem., (1999) 274, 12611). Each of the references cited is expressly incorporated by reference herein in its entirety.
  • An inhibitor may be administered directly or with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the inhibitor to patients with, or presymptomatic for, eosinophilic esophagitis.
  • any appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intranasal, aerosol, or oral administration.
  • Therapeutic formulations may be in the form of solids, liquid solutions, or suspensions; for oral administration, formulations may be in the form of tablets (chewable, dissolvable, etc.), capsules (hard or soft gel), pills, syrups, elixirs, emulsions, etc.; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
  • a CCR3 antagonist is administered parenterally and/or orally.
  • Enteral formulations may contain thixotropic agents, flavoring agents, and other ingredients for enhancing organoleptic qualities.
  • Formulations for parenteral administration may, for example, contain excipients, including but not limited to pharmaceutically acceptable buffers, emulsifiers, surfactants, and electrolytes such as sodium chloride, as well as sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • excipients including but not limited to pharmaceutically acceptable buffers, emulsifiers, surfactants, and electrolytes such as sodium chloride, as well as sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Formulations for inhalation may also contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • excipients for example, lactose

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Abstract

A method to evaluate eosinophilic esophagitis based on information in an eosinophilic esophagitis transcriptome.

Description

    RELATED APPLICATION
  • This application is a Continuation in Part of U.S. application Ser. No. 11/721,127 filed Jun. 7, 2007, which claims priority from PCT/US2005/044456 filed Dec. 7, 2005, which claims priority from U.S. application Ser. No. 60/633,909 filed Dec. 7, 2004, each of which is expressly incorporated by reference herein in its entirety.
  • The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of Grant No. 2R01AI045898-05 awarded by the National Institutes of Health.
    • FIELD OF THE INVENTION
  • The invention is directed generally to evaluating and mitigating eosinophilic esophagitis.
    • BACKGROUND
  • Patients with eosinophilic esophagitis may have symptoms that include abdominal pain, difficulty swallowing, vomiting, failure to thrive and weight loss. In addition, allergy, particularly food allergy, is an associated finding in most patients, and many have concomitant asthma or other chronic respiratory disease. Diagnosis requires endoscopy, and diseased tissue shows characteristic punctate white surface dots associated with erythema, loss of vascular pattern, ulcers, or ringed trachea-like appearance.
  • Patients with eosinophilic esophagitis typically have elevated levels of eosinophils in esophageal tissue and peripheral blood. Eosinophils are one type of granulocytic leukocyte (white blood cell) or granulocyte that normally appears in the peripheral blood at a concentration of about 1-3% of total leukocytes. Their presence in tissues is normally primarily restricted to the gastrointestinal mucosa, i.e. the stomach and intestines. Eosinophil accumulation in the peripheral blood and tissues is a hallmark feature of an allergic response, and may cause potent pro-inflammatory effects or tissue remodeling. Because eosinophilic esophagitis is marked by infiltration of eosinophils, this condition may be linked to allergen exposure. Eosinophil accumulation occurs in other allergic diseases such as allergic rhinitis, asthma, and eczema as well as parasitic infections, certain types of malignancies, chronic inflammatory disorders such as inflammatory bowel disease, specific syndromes such as eosinophilic gastroenteritis, eosinophilic colitis, eosinophilic cellulitis, eosinophilic fascitis, and systemic diseases such as Churg Strauss syndrome, eosinophilic pneumonia, and the idiopathic hypereosinophilic syndrome.
  • Numerous mediators have been identified as eosinophil chemoattractants. These include diverse molecules such as lipid mediators (platelet activating factor (PAF), leukotrienes) and chemokines such as the eotaxin subfamily of chemokines. Chemokines are small secreted proteins produced by tissue cells and leukocytes that regulate leukocyte homing during homeostatic and inflammatory states. Two main subfamilies (CXC and CC chemokines) are distinguished depending upon the arrangement of the first two cysteine amino acids, either separated by one amino acid (CXC), or adjacent (CC).
  • Due to the increasing incidence of eosinophilic esophagitis, methods to mitigate eosinophilic esophagitis would be beneficial. In addition, because eosinophilic esophagitis is often confused with other disorders such as gastroesophageal reflux disease (GERD), but does not typically respond to anti-GERD therapy, it is important to develop diagnostic features that distinguish between eosinophilic esophagitis and GERD. Diagnosis currently requires endoscopy with subsequent biopsy and analysis of the excised tissue by a pathologist based on manual microscopic analysis, so that less invasive methods of diagnosing eosinophilic esophagitis would also be beneficial.
    • SUMMARY OF THE INVENTION
  • The terms normal individuals, individuals without eosinophilic esophagitis (EE), control group or controls, patients without EE, and normal patients are used synonymously. The terms individuals with EE, treated groups, EE patients, and patients with EE are used synonymously.
  • One embodiment of the invention is a method of assessing eosinophilic esophagitis (EE) in a patient by comparing the patient's blood concentration of eotaxin-3 to a normal concentration of eotaxin-3, where an increased concentration of eotaxin-3 indicates EE.
  • Another embodiment of the invention is a diagnostic assay for EE. One embodiment of the assay may include a test strip containing an anti-eotaxin-3 antibody and at least one reagent that indicates binding of the anti-eotaxin-3 antibody to eotaxin-3 present in a supranormal level in a biological sample. Detection may be by visual inspection for a chromogen, fluorogen, colloidal gold agglutination, luminescence, etc.
  • Another embodiment of the invention is a diagnostic method for EE where eotaxin-3 DNA, eotaxin-3 mRNA, and/or eotaxin-3 protein is present over a normal amount in a patient tissue, as an indicator of EE in the patient.
  • Another embodiment of the invention is a diagnostic method for EE where a frequency of single nucleotide polymorphisms (SNPs) in the eotaxin-3 gene above normal frequency is an indicator of EE or a marker of disease risk, prognosis, and/or a response to therapy.
  • Another embodiment of the invention is a method to mitigate EE by providing an inhibitor to eotaxin-3 and/or a receptor, such as CCR3, for binding eotaxin-3 in a cell, such as a mast cell or an eosinophil, under conditions sufficient to inhibit eotaxin-3 binding to the receptor.
  • Another embodiment of the invention is a gene expression profile for EE comprising SEQ. ID NOS. 1-1620.
  • Another embodiment of the invention is a method to evaluate EE by gene expression profiles, where evaluation encompasses assessment of disease propensity, of disease severity, of therapy efficacy, of therapy compliance, etc. In one embodiment, EE is evaluated by determining an expression profile of at least one gene in the esophagus of the patient, where the gene is selected from SEQ ID NOS. 1-1620. In one embodiment, EE is evaluated by determining an expression profile of at least one gene in the patient, where the gene is selected from group consisting of SEQ ID NOS. 1-1620. The expression profile of the selected gene(s) is then compared to the expression profile of that same gene in an individual that does not have EE. The patient's propensity for EE is evaluated by determining if the gene in the patient is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile in the individual without EE. This propensity is evaluated by determining the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed. The patient's propensity for EE is higher based on at least one of the farther the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are over-expressed or under-expressed. In one embodiment the gene is SEQ ID NO.1. In one embodiment, the patient lacks at least one clinical and/or physical symptoms of EE. In one embodiment, the cell is an esophageal cell.
  • Another embodiment of the invention is a method to evaluate a compound's contribution to the pathophysiology of EE. At least one cell, referred to as the test cell, is exposed to the compound, and an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in the cell(s) is compared to an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in a cell of an individual without EE, referred to as the control cell. The contribution of the compound to the pathophysiology of EE is evaluated by determining if the at least one gene in the test cell is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile of the control cell. The compound's contribution to the pathophysiology of EE is evaluated by determining the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed. The compound contributes more to the pathophysiology of EE based on at least one of the farther the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are over-expressed or under-expressed. In one embodiment, the cell is an esophageal cell. In one embodiment, based on the extent that the compound contributes to EE, therapeutics that antagonize the action of the compound may be used to treat EE.
  • Another embodiment of the invention is a method to evaluate an individual's response to therapy for EE. An expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in an esophagus of an individual exposed to therapy is compared to an expression profile of the same gene(s) from an individual without EE. The individual's response to therapy for EE is evaluated by determining if the at least one gene is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile from the individual without EE. The individual's response to therapy for EE is evaluated based on the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed. The individual is less responsive to therapy for EE based on at least one of the farther the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are expressed or under-expressed.
  • Another embodiment of the invention is a method to evaluate an individual's compliance with therapy for EE. An expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in an esophagus of an individual prescribed therapy for EE is compared to an expression profile of the same gene(s) from an individual without EE. The individual's compliance with therapy is evaluated by determining if the at least one gene is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile from the individual without EE. The individual's compliance with therapy is determined based on the extent that over-expression or under-expression exceeds 1.5, the identify of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed. The individual is less compliant with therapy for EE based on at least one of the father the over-expression or under-expression is from 1.5, the gene is from SEQ ID NO. 1-42, and/or the greater the number of genes that are over-expressed or under-expressed. That is, the gene expression is more like an individual with EE than a normal EE without EE.
  • Another embodiment of the invention is a method to evaluate whether an individual had EE prior to a current assessment. An expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 6, 35, 43, 61, 129, 1358, 1441, 1515, 1538, 1584, 1615, 1618, and 1620 in an esophagus of an individual is compared to the expression profile of the same gene(s) from an individual without EE. The individual's prior EE is evaluated by determining if the at least one gene is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile from the individual without EE. The likelihood of the individual having EE prior to the current assessment is determined based on the extent that over-expression or under-expression exceeds 1.5, the identity of the gene over-expressed or under-expressed, and/or the number of genes that are over-expressed or under-expressed. The individual is more likely to have had prior EE based on at least one of the farther the over-expression or under-expression is from 1.5, and/or the greater the number of genes that are over-expressed or under-expressed. In one embodiment, the individual does not have active EE when the method is performed.
  • These and other advantages will be apparent in light of the following figures and detailed description.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
  • FIG. 1 shows DNA microarray data of eotaxin-3 mRNA levels in esophageal tissue of normal patients and patients with eosinophilic esophagitis (EE).
  • FIG. 2 shows data from quantitative polymerase chain reaction analysis showing normalized eotaxin-3 mRNA levels in normal patients, patients with gastroesophageal reflux disease (GERD), and patients with EE.
  • FIG. 3 shows esophageal eosinophil concentration in control and allergen-induced wild-type mice, and allergen-induced mice lacking the gene encoding the CCR3 receptor.
  • FIG. 4 shows plasma concentrations of eotaxin-3 in normal patients and patients with EE.
  • FIG. 5 shows hierarchical cluster analysis of transcripts expressed in normal (NL), reflux (RE), and EE esophageal biopsies.
  • FIG. 6 shows fluticasone propionate treatment-resistant genes within the EE transcriptome.
    •  DETAILED DESCRIPTION
  • Methods of diagnosing, assessing, and mitigating eosinophilic esophagitis (EE) by modulating levels and activity of eotaxin-3 and by evaluating gene expression profiles are disclosed.
  • Eotaxin-3 is a CC chemokine with selective activity on eosinophils. For example, eotaxin-3 recruits and directs eosinophils to sites in the body, such as the esophagus, via chemoattraction. Additional chemokines have been identified in the genome that encode for CC chemokines with eosinophil-selective chemoattractant activity, and have been designated eotaxin-1 and eotaxin-2.
  • The activity of eotaxin-3 is mediated by the selective expression of an eotaxin receptor, CCR3, on eosinophils. CCR3 is a promiscuous receptor; it interacts with multiple ligands including macrophage chemoattractant proteins (MCP)-2, -3, and -4, RANTES (regulated upon activation normal T-cell expressed and secreted), and HCC-2 (MIP-5, leukotactin). The only ligands that signal exclusively through this receptor, however, are eotaxins-1, -2, and -3, accounting for the cellular selectivity of the eotaxins.
  • Esophageal tissue obtained from patients previously diagnosed with EE was analyzed. Diagnosis was based on analysis of excised tissue from endoscopic biopsy. Tissues from patients with EE, as well as patients not having EE (controls) were subjected to genome-wide microarray transcript profiling (Affymetrix GeneChip). All work was performed at the Core facility at Children's Hospital Medical Center (Cincinnati Ohio).
  • Briefly, RNA quality was first assessed using the Agilent bioanaiyzer (Agilent Technologies, Palo Alto Calif.). Only mRNA having a ratio of 28S/18S between 1.3 and 2 were subsequently used. RNA was converted to cDNA with Superscript choice for cDNA synthesis (Invitrogen, Carlsbad Calif.) and subsequently converted to biotinylated cRNA with Enzo High Yield RNA Transcript labeling kit (Enzo Diagnostics, Farmingdale N.Y.). After hybridization to the GeneChip (Affymetrix, Santa Clara Calif.), the chips were automatically washed and stained with streptavidin-phycoerythrin using a fluidics system. The chips were scanned with a Hewlett Packard GeneArray Scanner. Over 30,000 unique genes were screened.
  • Levels of gene transcripts were determined from data image files, using algorithms in the Microarray Analysis Suite software (Affymetrix). Levels from chip to chip were compared by global scaling. Each gene was typically represented by a probe set of 16 to 20 probe pairs. Each probe pair consisted of a perfect match oligonucleotide and a mismatch oligonucleotide that contained a one base mismatch at a central position. Two measures of gene expression were used, absolute call and average difference. Absolute call is a qualitative measure in which each gene is assigned a call of present, marginal or absent, based on the hybridization of the RNA to the probe set. Average difference is a quantitative measure of the level of gene expression, calculated by taking the difference between mismatch and perfect match of every probe pair and averaging the differences over the entire probe set. Data were normalized and an EE transcriptome gene list was created with results having p<0.01 (Welch t-test with or without false rate discovery) and ≧1.5-fold change.
  • FIG. 1 shows the normalized relative average difference of the gene encoding eotaxin-3 from normal patients and patients with EE. The microarray analysis identified eotaxin-3 as the top gene induced, indicating a role in EE. Eotaxin-1 and eotaxin-2 mRNA levels were not significantly increased in EE patients.
  • Quantitative polymerase chain reaction (PCR) using LightCycler technology (Roche Diagnostics Corp. Indianapolis Ind.) which involves a competitive amplification of cDNA prepared from esophageal RNA, known to one skilled in the art, was further utilized to validate the microarray analysis results. Levels of eotaxin-3 mRNA from normal patients, patients with gastroesophageal reflux disease (GERD), and patients with EE were compared. As shown in FIG. 2, eotaxin-3 mRNA was induced nearly 100-fold in patients with EE when normalized to a housekeeping gene GAPDH. Patients with GERD showed only slightly increased levels compared to normal patients. Levels of the other two eotaxin mRNA species (eotaxin-1 and eotaxin-2) were not increased in patient esophageal samples (data not shown), validating the specific role of eotaxin-3.
  • A murine model of EE was evaluated to determine the role of the eotaxin-3 receptor, CCR3. The model is disclosed in Mishra et al., J. Clin. Invest. (2001) 107, 83, which is expressly incorporated by reference herein in its entirety. Because EE is marked by infiltration of eosinophils, this condition may be linked to exposure to allergens. In support of this, animals models of EE were induced by allergen exposure to the respiratory tract. In brief, mice were exposed to repeated doses of intranasal Aspergillus fumigatus antigen (three doses a week) for three weeks. Subsequently, the mice were euthanized 18 hours after the last dose of allergen or saline control, and the esophagus was analyzed for the occurrence of EE.
  • Specifically, asthma was experimentally induced in wild-type and CCR3 knockout (KO) mice (a gift of Drs. Craig Gerard and Allison Humbles at Harvard Medical School) using Aspergillus fumigatus (ASP) as an allergen. Wild-type control mice received saline. The concentration of eosinophils was determined in the esophagus of allergen-induced wild-type mice (ASP wt), control wild-type mice (saline wt), and allergen-induced mice lacking the gene encoding CCR3 (ASP CCR3KO). The results are shown in FIG. 3.
  • The concentration of eosinophils in allergen-induced wild-type mice (ASP wt) was about 75 eosinophils per mm2. The concentration of eosinophils in allergen-induced CCR3KO mice (ASP CCR3KO) was about 4 eosinophils per mm2, similar to the eosinophil concentration in control wild-type mice (saline wt). The decreased concentration of eosinophils in allergen-induced CCR3KO mice compared to allergen-induced wild-type mice was statistically significant (p=0.04; Student's T-test). EE-related symptoms and/or pathology may be mitigated by mediating eosinophil chemotactic events using techniques such as those disclosed in U.S. Pat. No. 6,780,973, which is expressly incorporated by reference herein in its entirety. One example is a recombinant polypeptide capable of mediating eosinophil chemotactic events where the polypeptide includes a domain having a sequence which has at least 70% identity to full length murine eotaxin cDNA, full length guinea pig eotaxin cDNA, and/or human eotaxin DNA. Another example is reducing eotaxin activity using an antagonist such as an antieotaxin-3 antibody or eotaxin-1, -2, or -3 fragment, a purified antibody which binds specifically to a murine or human eotaxin-3 protein indicating an intact monoclonal or polyclonal antibody, an immunologically active antibody fragment, or a genetically engineered fragment. The antagonist may be an eotaxin-1, -2, or -3 polypeptide having a deletion of 1-10 N-terminal amino acids, or having an addition of 3-10 amino acids on the amino terminus.
  • The concentration of eotaxin-3 protein in plasma was elevated in patients with EE, compared to normal controls. Concentrations were determined using a commercially purchased sandwich ELISA kit (R&D Quantikine CCL-26 kit, R&D Systems Inc., Minneapolis Minn.). In blood anticoagulated with heparin, eotaxin-3 concentrations in plasma of normal patients were 29.43 pg/ml±15.4 pg/ml (n=6), and eotaxin-3 concentration in patients with eosinophilic esophagitis were 52.97 pg/ml±12 pg/ml (n=3) (p=0.055). In blood anticoagulated with ethylenediamine tetraacetic acid (EDTA), eotaxin-3 concentrations in plasma of normal patients were 8.3 pg/ml±7 pg/ml (n=15), and eotaxin-3 concentration in patients with eosinophilic esophagitis were 18.19 pg/ml±7 (n=4) (p=0.044). These data are shown in FIG. 4. Therefore, the blood concentration of eotaxin-3 in an individual may be compared to a normal level as a relatively non-invasive or minimally invasive indication of eosinophilic esophagitis. In one embodiment, a plasma concentration of eotaxin-3 of about 52.97 pg/ml±12 pg/ml in blood anticoagulated with heparin is indicative of EE. In another embodiment, a plasma concentration of eotaxin-3 of about 18.19 pg/ml±7 pg/ml in blood anticoagulated with EDTA is indicative of EE. These blood concentrations of eotaxin-3 may serve as a diagnostic marker, for which a less invasive diagnostic test for EE may be used, as further discussed below, to replace or serve as a preliminary indicator or whether a more invasive test, e.g. endoscopic biopsy, is warranted. The level of eotaxin-3 may also serve to determine if a specific therapy is mitigating EE, and thus may be used to monitor therapy. Similarly, the concentration or amount of eotaxin-3 DNA, eotaxin-3 mRNA, or eotaxin-3 protein over a normal amount in a patient tissue, such as blood or esophageal tissue, can be utilized further as an indicator of EE in the patient.
  • For evaluation of EE using clinical and/or physical assessment, biopsy tissues (obtained from the distal esophagus during routine endoscopy) were submerged in formalin for routine pathological analysis with hematoxylin and eosin staining. Diagnosis was established based on the maximum eosinophil count per high power field (hpf) and basal layer expansion according to method known in the art (e.g., established criteria in Rothenberg et al., Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy Clin Immunol 108 (2001) 891; Attwood et al., Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci 38 (1993)109; Fox et al., Eosinophilic esophagitis: it's not just kid's stuff. Gastrointest Endosc 56 (2002) 26, each of which is expressly incorporated by reference herein in its entirety. Normal individuals (NL), n=13, served as a control and were defined as having 0 eosinophils/hpf and no basal layer expansion. Individuals with EE (n=76) were defined as having >24 eosinophils/hpf and extensive basal layer hyperplasia (expansion to about >⅓ of epithelium). Whole genome wide expression analysis demonstrated an EE transcriptome comprising 1620 genes. That is, 1620 genes were expressed significantly differently in EE patients compared to normal individuals, meaning that, at p<0.01, these 1620 genes from EE patients, using a patient pool size of 89, of which 76 patients had been diagnosed with EE, and 13 patients were individuals without EE, were either up-regulated or down-regulated by ≧1.5 fold, compared to normal individuals (NL). The data were analyzed by cluster analysis and ordered (standard correlation (A) and distance (B)) using Genespring software. Results are shown in FIG. 5 and Table 1. In FIG. 5, down-regulated genes were depicted in blue; and up-regulated genes were depicted in red, with the magnitude of the gene change proportional to the intensity of the blue and/or red colors. Each column represented a separate individual and each line a gene. RNA from each patient was subjected to chip analysis using Affymetrix Human Genome U133 GeneChip plus 2.
  • TABLE 1
    The EE transcriptome
    Fold Genbank Accession SEQ ID
    Common Name Description Change number NO
    CCL26 Chemokine (C-C motif) ligand 26 62.73 NM_006072 1
    TNFAIP6 Tumor necrosis factor, alpha-induced 42.94 NM_007115 2
    protein 6
    ALOX15 Arachidonate 15-lipoxygenase 36.11 NM_001140 3
    APOBEC3A Apolipoprotein B mRNA editing enzyme, 24.37 NM_145699 4
    catalytic polypeptide-like 3A
    POSTN Periostin, osteoblast specific factor 23.42 NM_006475 5
    CDH26 Cadherin-like 26 23.28 NM_021810 6
    CXCL1 Chemokine (C—X—C motif) ligand 1 20.89 NM_001511 7
    (melanoma growth stimulating activity,
    alpha)
    NEFL Neurofilament, light polypeptide 68 kDa 17.68 NM_006158 8
    TMEM16A Transmembrane protein 16A 17.5 NM_018043 9
    SEQ_ID_#10 16.93 XM_293626 10
    PMCH Pro-melanin-concentrating hormone 16.04 NM_002674 11
    TMEM71 Hypothetical protein FLJ33069 15.06 NM_144649 12
    CPA3 Carboxypeptidase A3 (mast cell) 14.51 NM_001870 13
    LRRC31 Leucine rich repeat containing 31 12.48 NM_024727 14
    IGLC2 Immunoglobulin lambda joining 3 12.33 AK057174 15
    IGHD Immunoglobulin heavy constant delta 12.11 AK090461 16
    SEQ_ID_#17 11.46 XM_097433 17
    CLC Charcot-Leyden crystal protein 11.06 NM_001828 18
    SEQ_ID_#19 10.29 NG_000002 19
    CXCL6 Chemokine (C—X—C motif) ligand 6 10.24 NM_002993 20
    (granulocyte chemotactic protein 2)
    SEC6L1 SEC6-like 1 (S. cerevisiae) 8.878 NM_007277 21
    TCF12; HEB; HTF4; Homo sapiens mRNA; cDNA 8.833 BX647333 22
    HsT17266 DKFZp686K1288 (from clone
    DKFZp686K1288).
    IGJ Immunoglobulin J polypeptide, linker 8.768 NM_144646 23
    protein for immunoglobulin alpha and mu
    polypeptides
    C1orf178 Chromosome
    1 open reading frame 178 8.681 NM_001010922 24
    PHLDB2 Pleckstrin homology-like domain, family 8.485 NM_145753 25
    B, member 2
    GLDC Glycine dehydrogenase (decarboxylating; 8.382 NM_000170 26
    glycine decarboxylase, glycine cleavage
    system protein P)
    EPPK1 Epiplakin 1 7.894 NM_031308 27
    UBD Ubiquitin D 7.854 NM_006398 28
    SUSD2 Sushi domain containing 2 7.725 NM_019601 29
    CTSC synonyms: HMS, PLS, CPPI, DPP1, DPPI, 7.56 NM_148170 30
    PALS; isoform b precursor is encoded by
    transcript variant 2; dipeptidyl-peptidase
    I; dipeptidyl transferase; cathepsin J;
    Papillon-Lefevre syndrome;
    go_component: lysosome [goid 0005764]
    [evidence TAS] [pmid 7665576];
    go_function: dipeptidyl-peptidase I
    activity [goid 0004214] [evidence IEA];
    go_function: cysteine-type endopeptidase
    activity [goid 0004197] [evidence IEA];
    go_process: immune response [goid
    0006955] [evidence TAS] [pmid
    9092576]; go_process: proteolysis and
    peptidolysis [goid 0006508] [evidence
    NR]; Homo sapiens cathepsin C (CTSC),
    transcript variant 2, mRNA.
    TPSB2 Tryptase beta 2 7.199 NM_003294 31
    SLC26A4 Solute carrier family 26, member 4 7.192 NM_000441 32
    SAMSN1 SAM domain, SH3 domain and nuclear 7.119 NM_022136 33
    localisation signals, 1
    TRPM6 Transient receptor potential cation 6.979 NM_017662 34
    channel, subfamily M, member 6
    IF I factor (complement) 6.673 NM_000204 35
    IL8 Interleukin 8 6.664 NM_000584 36
    FLJ39117 Repetin 6.256 XM_371312 37
    HRH1 Histamine receptor H1 6.208 NM_000861 38
    MUC4 Mucin 4, tracheobronchial 6.139 NM_004532 39
    KCNJ2 Potassium inwardly-rectifying channel, 6.061 NM_000891 40
    subfamily J, member 2
    IFRG28 28 kD interferon responsive protein 6.035 NM_022147 41
    GPR160 G protein-coupled receptor 160 5.995 NM_014373 42
    SEQ_ID_#43 Transcribed locus 5.944 CA314541 43
    CA2 Carbonic anhydrase II 5.681 NM_000067 44
    CD200R1 CD200 receptor 1 5.587 NM_138806 45
    BF B-factor, properdin 5.507 NM_001710 46
    SCUBE2 Signal peptide, CUB domain, EGF-like 2 5.502 NM_020974 47
    MS4A2 Membrane-spanning 4-domains, 5.471 NM_000139 48
    subfamily A, member 2 (Fc fragment of
    IgE, high affinity I, receptor for; beta
    polypeptide)
    MMP12 Matrix metalloproteinase 12 (macrophage 5.411 NM_002426 49
    elastase)
    PGDS Prostaglandin D2 synthase, hematopoietic 5.312 NM_014485 50
    SEQ_ID_#51 UI-H-DF1-aug-p-10-0-UI.s1 5.278 BM993907 51
    NCI_CGAP_DF1 Homo sapiens cDNA
    clone IMAGE: 5869305 3′, mRNA
    sequence.
    SEQ_ID_#52 Transcribed locus 5.183 BQ004901 52
    CHL1 Cell adhesion molecule with homology to 5.1 NM_006614 53
    L1CAM (close homolog of L1)
    C9orf150 Chromosome 9 open reading frame 150 4.944 NM_203403 54
    APOL1 Apolipoprotein L, 1 4.935 NM_003661 55
    SEQ_ID_#56 LOC441801 4.841 BC037919 56
    CH25H Cholesterol 25-hydroxylase 4.828 NM_003956 57
    SEQ_ID_#58 4.822 XM_294092 58
    SIDT1 Hypothetical protein FLJ21394 4.822 NM_017699 59
    SLC28A3 Solute carrier family 28 (sodium-coupled 4.775 NM_022127 60
    nucleoside transporter), member 3
    UPK1B Uroplakin 1B 4.732 NM_006952 61
    IL13RA2 Interleukin 13 receptor, alpha 2 4.636 NM_000640 62
    PKP2 Plakophilin 2 4.627 NM_001005242 63
    MSLN Mesothelin 4.616 NM_005823 64
    SEQ_ID_#65 4.547 XM_059368 65
    SLC6A14 Solute carrier family 6 (amino acid 4.539 NM_007231 66
    transporter), member 14
    NTRK2 Neurotrophic tyrosine kinase, receptor, 4.513 NM_001007097 67
    type 2
    VGLL1 Vestigial like 1 (Drosophila) 4.453 NM_016267 68
    SPON1 Spondin 1, extracellular matrix protein 4.431 NM_006108 69
    SEQ_ID_#70 UI-H-DF1-aug-p-10-0-UI.s1 4.409 BM993907 70
    NCI_CGAP_DF1 Homo sapiens cDNA
    clone IMAGE: 5869305 3′, mRNA
    sequence.
    PRRX1 Paired related homeobox 1 4.375 NM_006902 71
    SEQ_ID_#72 Transcribed locus 4.374 AW978130 72
    SERPINB4 Serine (or cysteine) proteinase inhibitor, 4.328 NM_002974 73
    clade B (ovalbumin), member 4
    RGS13 Regulator of G-protein signalling 13 4.306 NM_002927 74
    SLC16A1 AKR7 family pseudogene 4.285 NM_003051 75
    LOC340061 Hypothetical protein LOC340061 4.211 NM_198282 76
    TIMP1 Tissue inhibitor of metalloproteinase 1 4.158 NM_003254 77
    (erythroid potentiating activity,
    collagenase inhibitor)
    SFRP1 Secreted frizzled-related protein 1 4.098 NM_003012 78
    GCNT3 Glucosaminyl (N-acetyl) transferase 3, 4.078 NM_004751 79
    mucin type
    SE57-1 CTCL tumor antigen se57-1 4.055 NM_025214 80
    GRK5 G protein-coupled receptor kinase 5 3.995 NM_005308 81
    SEQ_ID_#82 UI-H-DF1-aug-p-10-0-UI.s1 3.968 BM993907 82
    NCI_CGAP_DF1 Homo sapiens cDNA
    clone IMAGE: 5869305 3′, mRNA
    sequence.
    ADRBK2 Adrenergic, beta, receptor kinase 2 3.932 NM_005160 83
    HTR2B 5-hydroxytryptamine (serotonin) receptor 3.91 NM_000867 84
    2B
    IFI35 Interferon-induced protein 35 3.885 NM_005533 85
    IFI27 Interferon, alpha-inducible protein 27 3.873 NM_005532 86
    LOC440449 Hypothetical gene supported by 3.856 XM_498675 87
    AF086204
    TPK1 Thiamin pyrophosphokinase 1 3.806 NM_022445 88
    GALNT4 UDP-N-acetyl-alpha-D- 3.753 NM_003774 89
    galactosamine:polypeptide N-
    acetylgalactosaminyltransferase 4
    (GalNAc-T4)
    PDZK1IP1 PDZK1 interacting protein 1 3.677 NM_005764 90
    LOC130576 Hypothetical protein LOC130576 3.669 NM_177964 91
    SLC2A3 Solute carrier family 2 (facilitated glucose 3.657 NM_006931 92
    transporter), member 3
    FOXE1 Forkhead box E1 (thyroid transcription 3.65 NM_004473 93
    factor 2)
    GABRP Gamma-aminobutyric acid (GABA) A 3.65 NM_014211 94
    receptor, pi
    SEQ_ID_#95 Transcribed locus 3.633 BM988338 95
    TNFSF13 Tumor necrosis factor (ligand) 3.62 NM_003808 96
    superfamily, member 12
    IGFBP3 Insulin-like growth factor binding protein 3 3.605 NM_000598 97
    LHFPL2 Lipoma HMGIC fusion partner-like 2 3.591 NM_005779 98
    CYP7B1 Cytochrome P450, family 7, subfamily B, 3.555 NM_004820 99
    polypeptide 1
    SLC18A2 Solute carrier family 18 (vesicular 3.541 NM_003054 100
    monoamine), member 2
    KITLG KIT ligand 3.538 NM_000899 101
    LITAF Lipopolysaccharide-induced TNF factor 3.492 NM_004862 102
    CDC42EP5 CDC42 effector protein (Rho GTPase 3.479 NM_145057 103
    binding) 5
    KRT23 Keratin 23 (histone deacetylase inducible) 3.475 NM_015515 104
    EMILIN2 Elastin microfibril interfacer 2 3.473 NM_032048 105
    TFPI Tissue factor pathway inhibitor 3.455 NM_006287 106
    (lipoprotein-associated coagulation
    inhibitor)
    LOX Lysyl oxidase 3.448 NM_002317 107
    PGBD5 PiggyBac transposable element derived 5 3.439 NM_024554 108
    IL17RB Interleukin 17 receptor B 3.426 NM_018725 109
    LOC91353 Similar to omega protein 3.416 NM_001013618 110
    HS3ST1 Heparan sulfate (glucosamine) 3-O- 3.402 NM_005114 111
    sulfotransferase 1
    RARRES3 Retinoic acid receptor responder 3.397 NM_004585 112
    (tazarotene induced) 3
    HAS3 Decreased expression in renal and 3.391 NM_005329 113
    prostate
    GPRC5B G protein-coupled receptor, family C, 3.384 NM_016235 114
    group 5, member B
    NRXN1 Neurexin 1 3.372 NM_004801 115
    SEQ_ID_#116 Transcribed locus 3.363 AW195474 116
    LOXL4 Lysyl oxidase-like 4 3.336 NM_032211 117
    PRG1 Proteoglycan 1, secretory granule 3.295 NM_002727 118
    MFHAS1 Malignant fibrous histiocytoma amplified 3.29 NM_004225 119
    sequence 1
    SECTM1 Secreted and transmembrane 1 3.282 NM_003004 120
    CISH Cytokine inducible SH2-containing protein 3.274 NM_145071 121
    CFHL1 Complement factor H-related 1 3.251 NM_002113 122
    pseudogene
    HDC Histidine decarboxylase 3.243 NM_002112 123
    SIGLEC6 Sialic acid binding Ig-like lectin 6 3.199 NM_001245 124
    GPR110 G protein-coupled receptor 110 3.193 NM_153840 125
    SCIN Scinderin 3.17 NM_033128 126
    SGK Serum/glucocorticoid regulated kinase 3.139 NM_005627 127
    SH3RF2 SH3 domain containing ring finger 2 3.122 NM_152550 128
    SH2D1B SH2 domain containing 1B 3.098 NM_053282 129
    Cep72 Centrosomal protein 72 kDa 3.081 NM_018140 130
    FETUB Fetuin B 3.065 NM_014375 131
    RGS1 Regulator of G-protein signalling 1 3.056 NM_002922 132
    APOBEC3B Apolipoprotein B mRNA editing enzyme, 3.039 NM_004900 133
    catalytic polypeptide-like 3D
    MGC48998 Chromosome 1 open reading frame 110 3.036 NM_178550 134
    CDH3 Cadherin 3, type 1, P-cadherin (placental) 3.026 NM_001793 135
    DPYD Dihydropyrimidine dehydrogenase 3.015 NM_000110 136
    EGLN3 Egl nine homolog 3 (C. elegans) 3.003 NM_022073 137
    PTGES Prostaglandin E synthase 2.972 NM_004878 138
    KIAA1126 KIAA1126 protein 2.944 AB032952 139
    LOH11CR2A Loss of heterozygosity, 11, chromosomal 2.938 NM_198315 140
    region 2, gene A
    CYP2S1 Cytochrome P450, family 2, subfamily S, 2.911 NM_030622 141
    polypeptide 1
    SEQ_ID_#142 UI-E-CL1-afe-h-18-0-UI.r1 UI-E-CL1 2.896 BM703543 142
    Homo sapiens cDNA clone UI-E-CL1-afe-
    h-18-0-UI 5′, mRNA sequence.
    LBH Likely ortholog of mouse limb-bud and 2.895 NM_030915 143
    heart gene
    MGC35033 Hypothetical protein MGC35033 2.875 NM_152319 144
    CTSG Cathepsin G 2.869 NM_001911 145
    SEQ_ID_#146 2.864 XM_375695 146
    STOM Stomatin 2.846 NM_004099 147
    PSMB9 Proteasome (prosome, macropain) 2.845 NM_002800 148
    subunit, beta type, 9 (large
    multifunctional protease 2)
    ATF3 isoform 3 is encoded by transcript variant 2.844 NM_001030287 149
    3; ATF3deltaZip3; ATF3deltaZip2c;
    go_component: nucleus [goid 0005634]
    [evidence IEA]; go_function: DNA binding
    [goid 0003677] [evidence IEA];
    go_function: transcription factor activity
    [goid 0003700] [evidence TAS] [pmid
    7515060]; go_function: transcription
    corepressor activity [goid 0003714]
    [evidence TAS] [pmid 7515060];
    go_process: transcription [goid 0006350]
    [evidence IEA]; go_process: regulation of
    transcription, DNA-dependent [goid
    0006355] [evidence IEA]; Homo sapiens
    activating transcription factor 3 (ATF3),
    transcript variant 3, mRNA.
    MMP28 Matrix metalloproteinase 28 2.839 NM_024302 150
    SLC15A1 Solute carrier family 15 (oligopeptide 2.792 NM_005073 151
    transporter), member 1
    AIM2 Absent in melanoma 2 2.788 NM_004833 152
    KIT V-kit Hardy-Zuckerman 4 feline sarcoma 2.776 NM_000222 153
    viral oncogene homolog
    IL15 Interleukin 15 2.772 NM_000585 154
    RASGRP1 RAS guanyl releasing protein 1 (calcium 2.769 NM_005739 155
    and DAG-regulated)
    SLC27A2 Solute carrier family 27 (fatty acid 2.766 NM_003645 156
    transporter), member 2
    IFIT3 Interferon-induced protein with 2.763 NM_001549 157
    tetratricopeptide repeats 3
    LRRC8D Leucine rich repeat containing 8 family, 2.761 NM_018103 158
    member D
    COL8A2 Collagen, type VIII, alpha 2 2.756 NM_005202 159
    DUOX1 Dual oxidase 1 2.755 NM_017434 160
    AYTL3 PLSC domain containing protein 2.749 NM_153613 161
    F13A1 Coagulation factor XIII, A1 polypeptide 2.746 NM_000129 162
    ACSL5 Acyl-CoA synthetase long-chain family 2.745 NM_016234 163
    member 5
    GCNT2 Glucosaminyl (N-acetyl) transferase 2, I- 2.742 NM_001491 164
    branching enzyme
    SEQ_ID_#165 Transcribed locus, moderately similar to 2.732 BM929354 165
    XP_517655.1 PREDICTED: similar to
    KIAA0825 protein [Pan troglodytes]
    TMPRSS4 Transmembrane protease, serine 4 2.719 NM_019894 166
    MRC1 Mannose receptor, C type 1 2.717 NM_002438 167
    NCF2 Neutrophil cytosolic factor 2 (65 kDa, 2.712 NM_000433 168
    chronic granulomatous disease,
    autosomal 2)
    CSF2RB Colony stimulating factor 2 receptor, 2.707 NM_000395 169
    beta, low-affinity (granulocyte-
    macrophage)
    GULP1 GULP, engulfment adaptor PTB domain 2.691 NM_016315 170
    containing 1
    SCUBE1 Signal peptide, CUB domain, EGF-like 1 2.689 NM_173050 171
    NFE2L3 Nuclear factor (erythroid-derived 2)-like 3 2.688 NM_004289 172
    PSMB8 Proteasome (prosome, macropain) 2.687 NM_004159 173
    subunit, beta type, 8 (large
    multifunctional protease 7)
    LY96 Lymphocyte antigen 96 2.678 NM_015364 174
    PSTPIP2 Proline-serine-threonine phosphatase 2.675 NM_024430 175
    interacting protein 2
    CTSS Cathepsin S 2.67 NM_004079 176
    GGH Gamma-glutamyl hydrolase (conjugase, 2.665 NM_003878 177
    folylpolygammaglutamyl hydrolase)
    SERPINE2 Serine (or cysteine) proteinase inhibitor, 2.66 NM_006216 178
    clade E (nexin, plasminogen activator
    inhibitor type 1), member 2
    GALNT5 UDP-N-acetyl-alpha-D- 2.648 NM_014568 179
    galactosamine:polypeptide N-
    acetylgalactosaminyltransferase 5
    (GalNAc-T5)
    CNTN4 Contactin 4 2.643 NM_175607 180
    TPPP Brain-specific protein p25 alpha 2.639 NM_007030 181
    ZDHHC11 Zinc finger, DHHC-type containing 11 2.631 NM_024786 182
    BCL2A1 BCL2-related protein A1 2.621 NM_004049 183
    GRM7 Glutamate receptor, metabotropic 7 2.62 BC009905 184
    SEQ_ID_#185 UI-H-BI4-apt-c-08-0-UI.s1 2.62 BF511924 185
    NCI_CGAP_Sub8 Homo sapiens cDNA
    clone IMAGE: 3088503 3′, mRNA
    sequence.
    SEQ_ID_#186 Transcribed locus 2.617 BF025845 186
    TSPAN3 Tetraspanin 3 2.614 NM_005724 187
    ADAM28 A disintegrin and metalloproteinase 2.613 NM_014265 188
    domain 28
    SEPX1 Selenoprotein X, 1 2.611 NM_016332 189
    IL27RA Interleukin 27 receptor, alpha 2.606 NM_004843 190
    NAV1 Neuron navigator 1 2.603 NM_020443 191
    MET Met proto-oncogene (hepatocyte growth 2.592 NM_000245 192
    factor receptor)
    SEQ_ID_#193 cs100c01.y1 Human Retinal pigment 2.591 CA389545 193
    epithelium/choroid cDNA (Un-normalized,
    unamplified): cs Homo sapiens cDNA
    clone cs100c01
    5′, mRNA sequence.
    SOCS3 Suppressor of cytokine signaling 3 2.589 NM_003955 194
    ID3 Inhibitor of DNA binding 3, dominant 2.584 NM_002167 195
    negative helix-loop-helix protein
    BID BH3 interacting domain death agonist 2.582 NM_001196 196
    THEDC1 Thioesterase domain containing 1 2.568 NM_018324 197
    LR8 LR8 protein 2.564 NM_014020 198
    CEL Carboxyl ester lipase (bile salt-stimulated 2.557 NM_001807 199
    lipase)
    CALML4 2.555 NM_001031733 200
    LOC387882 LOC387882 hypothetical protein 2.551 NM_207376 201
    NEK6 NIMA (never in mitosis gene a)-related 2.513 NM_014397 202
    kinase 6
    NCF1 Neutrophil cytosolic factor 1 (47 kDa, 2.509 NM_000265 203
    chronic granulomatous disease,
    autosomal 1)
    DDX58 DEAD (Asp-Glu-Ala-Asp) box polypeptide 2.506 NM_014314 204
    58
    CLDN23 Claudin 23 2.505 NM_194284 205
    FA2H Fatty acid 2-hydroxylase 2.497 NM_024306 206
    LOC286002 Hypothetical protein LOC286002 2.483 BC037315 207
    IFITM3 Interferon induced transmembrane 2.456 NM_021034 208
    protein 3 (1-8U)
    MDK Midkine (neurite growth-promoting factor 2.45 NM_001012333 209
    2)
    KIAA1337 Patched domain containing 2 2.445 XM_052561 210
    VDR Vitamin D (1,25-dihydroxyvitamin D3) 2.441 NM_000376 211
    receptor
    MGC14595 Hypothetical protein MGC14595 2.44 NM_032334 212
    CHKB Choline kinase beta 2.433 NM_152253 213
    APOL3 Apolipoprotein L, 3 2.426 NM_014349 214
    EDAR Ectodysplasin A receptor 2.425 NM_022336 215
    SEQ_ID_#216 CDNA FLJ31134 fis, clone IMR322000984 2.423 AK095590 216
    BRDG1 BCR downstream signaling 1 2.418 NM_012108 217
    FMO1 Flavin containing monooxygenase 1 2.412 NM_002021 218
    ASS Argininosuccinate synthetase 2.41 NM_000050 219
    GPRC5A G protein-coupled receptor, family C, 2.406 NM_003979 220
    group 5, member A
    LOC113179 Secretory carrier membrane protein 4 2.403 NM_138422 221
    TAPBP TAP binding protein (tapasin) 2.401 NM_003190 222
    UTS2 Urotensin 2 2.401 NM_006786 223
    LYPDC1 LY6/PLAUR domain containing 1 2.399 NM_144586 224
    MICB MHC class I polypeptide-related sequence B 2.394 NM_005931 225
    GPX4 Glutathione peroxidase 4 (phospholipid 2.393 NM_002085 226
    hydroperoxidase)
    TMCC3 Transmembrane and coiled-coil domain 2.39 NM_020698 227
    family 3
    TRIM22 Tripartite motif-containing 22 2.387 NM_006074 228
    SUV420H1 Suppressor of variegation 4-20 homolog 2.384 NM_017635 229
    1 (Drosophila)
    CFH Complement factor H 2.383 NM_001014975 230
    FLJ41603 FLJ41603 protein 2.378 NM_001001669 231
    SLC4A11 Solute carrier family 4, sodium 2.363 NM_032034 232
    bicarbonate transporter-like, member 11
    C1QB Complement component 1, q 2.351 NM_000491 233
    subcomponent, beta polypeptide
    FLJ35880 Hypothetical protein FLJ35880 2.349 NM_153264 234
    IGLL3; 16.1 Human germline gene 16.1 for Ig lambda 2.342 X03529 235
    L-chain C region (IgL-C16.1).
    SEQ_ID_#239 yc17g11.s1 Stratagene lung (#937210) 2.342 T70087 236
    Homo sapiens cDNA clone IMAGE: 80996
    3′, mRNA sequence.
    PLAUR Plasminogen activator, urokinase receptor 2.334 NM_001005377 237
    OR2A20P Olfactory receptor, family 2, subfamily A, 2.327 BC016940 238
    member 20 pseudogene
    MAP3K14 Mitogen-activated protein kinase kinase 2.318 NM_003954 239
    kinase 14
    GATA2 GATA binding protein 2 2.315 NM_032638 240
    BIRC4BP XIAP associated factor-1 2.315 NM_017523 241
    LOC388610 Hypothetical LOC388610 2.311 NM_001013642 242
    SEQ_ID_#243 AGENCOURT_6466806 NIH_MGC_88 2.308 BM479034 243
    Homo sapiens cDNA clone
    IMAGE: 5561432 5′, mRNA sequence.
    SOCS1 Suppressor of cytokine signaling 1 2.306 NM_003745 244
    SEQ_ID_#245 oc22e04.s1 NCI_CGAP_GCB1 Homo 2.303 AA806368 245
    sapiens cDNA clone IMAGE: 1350462 3′
    similar to contains Alu repetitive
    element; contains element PTR5 repetitive
    element;, mRNA sequence.
    SDPR Serum deprivation response 2.293 NM_004657 246
    (phosphatidylserine binding protein)
    HLF Hepatic leukemia factor 2.283 NM_002126 247
    SCARA3 Scavenger receptor class A, member 3 2.282 NM_182826 248
    SMILE SMILE protein 2.28 NM_181783 249
    FGG Fibrinogen gamma chain 2.272 NM_021870 250
    IFITM1 Interferon induced transmembrane 2.269 NM_003641 251
    protein 1 (9-27)
    CASP7 Caspase 7, apoptosis-related cysteine 2.266 NM_001227 252
    protease
    SEQ_ID_#253 Transcribed locus 2.264 CA306881 253
    PSMB10 Proteasome (prosome, macropain) 2.261 NM_002801 254
    subunit, beta type, 10
    UCP2 Uncoupling protein 2 (mitochondrial, 2.259 NM_003355 255
    proton carrier)
    IGSF4 Immunoglobulin superfamily, member 4 2.258 NM_014333 256
    RARB Retinoic acid receptor, beta 2.253 NM_000965 257
    LRP1 Low density lipoprotein-related protein 1 2.248 NM_002332 258
    (alpha-2-macroglobulin receptor)
    IFITM2 Interferon induced transmembrane 2.244 NM_006435 259
    protein 2 (1-8D)
    PARP14 Poly (ADP-ribose) polymerase family, 2.243 NM_017554 260
    member 14
    SOS1 Son of sevenless homolog 1 (Drosophila) 2.243 NM_005633 261
    NTRK3 Neurotrophic tyrosine kinase, receptor, 2.24 NM_002530 262
    type 3
    PRICKLE2 Prickle-like 2 (Drosophila) 2.237 NM_198859 263
    ARMCX3 Armadillo repeat containing, X-linked 3 2.234 NM_016607 264
    ECGF1 Endothelial cell growth factor 1 (platelet- 2.221 NM_001953 265
    derived)
    TNS4 Tensin 4 2.216 NM_032865 266
    FBXO6 F-box protein 6 2.216 NM_018438 267
    APOL2 Apolipoprotein L, 2 2.213 NM_030882 268
    LY75 Lymphocyte antigen 75 2.212 NM_002349 269
    C10orf128 Chromosome 10 open reading frame 128 2.198 BC047724 270
    RRM2 Ribonucleotide reductase M2 polypeptide 2.197 NM_001034 271
    GPCR5A G protein-coupled receptor, family C, 2.197 NM_003979 272
    group 5, member A
    HSPA5BP1 Heat shock 70 kDa protein 5 (glucose- 2.193 NM_017870 273
    regulated protein, 78 kDa) binding protein 1
    GLCCI1; GIG18 synonym: GIG18; Homo sapiens 2.191 XM_166529 274
    glucocorticoid induced transcript 1
    (GLCCI1), mRNA.
    CD52 CD52 antigen (CAMPATH-1 antigen) 2.184 NM_001803 275
    ADA Adenosine deaminase 2.183 NM_000022 276
    CXCL16 Chemokine (C—X—C motif) ligand 16 2.179 NM_022059 277
    IFIH1 Interferon induced with helicase C domain 1 2.174 NM_022168 278
    ZSWIM5 Zinc finger, SWIM-type containing 5 2.169 XM_046581 279
    VMP1 Transmembrane protein 49 2.168 NM_030938 280
    UBE2L6 Ubiquitin-conjugating enzyme E2L 6 2.164 NM_004223 281
    ARHGAP8; PRR5; Rho GTPase activating protein 8 2.164 NM_017701 282
    PP610; BPGAP1;
    FLJ20185
    IRF1 Interferon regulatory factor 1 2.161 NM_002198 283
    C1orf188 Hypothetical protein FLJ32096 2.157 NM_173795 284
    IFI30 Interferon, gamma-inducible protein 30 2.155 NM_006332 285
    PLCD3 Phospholipase C, delta 3 2.152 NM_133373 286
    WFDC5 WAP four-disulfide core domain 5 2.148 NM_145652 287
    SEQ_ID_#288 AGENCOURT_8217637 2.146 BQ717725 288
    Lupski_sympathetic_trunk Homo sapiens
    cDNA clone IMAGE: 6187901 5′, mRNA
    sequence.
    SIGLECP3 Sialic acid binding Ig-like lectin, 2.144 BC035688 289
    pseudogene 3
    IFPS Ifapsoriasin 2.142 NM_001014342 290
    CD14 CD14 antigen 2.138 NM_000591 291
    LOC441168 Hypothetical protein LOC441168 2.136 NM_001010919 292
    FCER1G Fc fragment of IgE, high affinity I, 2.135 NM_004106 293
    receptor for; gamma polypeptide
    CD44 CD44 antigen (homing function and 2.132 NM_000610 294
    Indian blood group system)
    SEQ_ID_#295 CDNA FLJ44380 fis, clone TRACH3035482 2.128 AK126351 295
    STAB1 Stabilin 1 2.127 NM_015136 296
    ITGAM Integrin, alpha M (complement 2.126 NM_000632 297
    component receptor 3, alpha; also known
    as CD11b (p170), macrophage antigen
    alpha polypeptide)
    CBX6 Chromobox homolog 6 2.126 NM_014292 298
    CYP2E1 Cytochrome P450, family 2, subfamily E, 2.118 NM_000773 299
    polypeptide 1
    C1orf74 Chromosome 1 open reading frame 74 2.117 NM_152485 300
    LILRB1 Leukocyte immunoglobulin-like receptor, 2.115 NM_006669 301
    subfamily B (with TM and ITIM domains),
    member 1
    BAK1 BCL2-antagonist/killer 1 2.114 NM_001188 302
    HCP5 HLA complex P5 2.113 NM_006674 303
    PLA2G3 Phospholipase A2, group III 2.112 NM_015715 304
    NXN Nucleoredoxin 2.107 NM_022463 305
    RRAS Related RAS viral (r-ras) oncogene 2.094 NM_006270 306
    homolog
    ESR1 Estrogen receptor 1 2.088 NM_000125 307
    LOC152485 Hypothetical protein LOC152485 2.086 NM_178835 308
    PITX2 Paired-like homeodomain transcription 2.085 NM_000325 309
    factor 2
    SLCO3A1 Solute carrier organic anion transporter 2.081 NM_013272 310
    family, member 3A1
    PARP12 Poly (ADP-ribose) polymerase family, 2.078 NM_022750 311
    member 12
    TAP1 Transporter 1, ATP-binding cassette, sub- 2.076 NM_000593 312
    family B (MDR/TAP)
    SEQ_ID_#313 Transcribed locus 2.075 BU689688 313
    RPRC1 Arginine/proline rich coiled-coil 1 2.074 NM_018067 314
    BTN3A3 Butyrophilin, subfamily 3, member A3 2.073 NM_006994 315
    UBE1L Ubiquitin-activating enzyme E1-like 2.07 NM_003335 316
    RRAD Ras-related associated with diabetes 2.069 NM_004165 317
    PLCE1 Phospholipase C, epsilon 1 2.069 NM_016341 318
    SEQ_ID_#319 601123374F1 NIH_MGC_5 Homo sapiens 2.069 BE749174 319
    cDNA clone IMAGE: 3348067 5′, mRNA
    sequence.
    CAPN14 Calpain 14 2.067 AK092257 320
    ELOVL5 ELOVL family member 5, elongation of 2.065 NM_021814 321
    long chain fatty acids (FEN1/Elo2,
    SUR4/Elo3-like, yeast)
    GPR143 G protein-coupled receptor 143 2.06 NM_000273 322
    SMTN Smoothelin 2.046 NM_134269 323
    FLJ14466 Hypothetical protein FLJ14466 2.045 NM_032790 324
    LOC285016; synonyms: PRO1097, RGPG542; Homo 2.045 XM_211736 325
    PRO1097; RGPG542 sapiens hypothetical protein LOC285016
    (LOC285016), mRNA.
    APOL6 Apolipoprotein L, 6 2.042 NM_030641 326
    ADAM8 A disintegrin and metalloproteinase 2.041 NM_001109 327
    domain 8
    C1orf186 Hypothetical gene supported by 2.035 NM_001007544 328
    AK122631; BC071785
    ABHD4 Abhydrolase domain containing 4 2.03 NM_022060 329
    GSDML Gasdermin-like 2.029 NM_018530 330
    SEQ_ID_#331 UI-H-BI4-apu-h-06-0-UI.s1 2.029 BF512055 331
    NCI_CGAP_Sub8 Homo sapiens cDNA
    clone IMAGE: 3088762 3′, mRNA
    sequence.
    MYCPBP C-myc promoter binding protein 2.028 NM_005848 332
    C1QA Complement component 1, q 2.023 NM_015991 333
    subcomponent, alpha polypeptide
    SLC16A2 Solute carrier family 16 (monocarboxylic 2.019 NM_006517 334
    acid transporters), member 2
    C10orf47 Chromosome 10 open reading frame 47 2.019 NM_153256 335
    GBP4 Guanylate binding protein 4 2.018 NM_052941 336
    ARHGEF6 Rac/Cdc42 guanine nucleotide exchange 2.013 NM_004840 337
    factor (GEF) 6
    LILRB2 Leukocyte immunoglobulin-like receptor, 2.012 NM_005874 338
    subfamily B (with TM and ITIM domains),
    member 2
    SEQ_ID_#339 2.009 AL121896 339
    NFKBIE Nuclear factor of kappa light polypeptide 2.007 NM_004556 340
    gene enhancer in B-cells inhibitor, epsilon
    SEQ_ID_#341 EST387291 MAGE resequences, MAGN 2.007 AW975183 341
    Homo sapiens cDNA, mRNA sequence.
    EHD2 EH-domain containing 2 2.004 NM_014601 342
    CCDC34 NY-REN-41 antigen 2.004 NM_030771 343
    BAZ2A Bromodomain adjacent to zinc finger 1.992 NM_013449 344
    domain, 2A
    CAPN3 Glucosidase, alpha; neutral C 1.989 NM_000070 345
    MVP Major vault protein 1.988 NM_005115 346
    SIGLEC10 Sialic acid binding Ig-like lectin 10 1.988 NM_033130 347
    ARID5B AT rich interactive domain 5B (MRF1-like) 1.988 AI289774 348
    ZC3H12A Zinc finger CCCH-type containing 12A 1.987 NM_025079 349
    AP2M1 Adaptor-related protein complex 2, mu 1 1.982 NM_001025205 350
    subunit
    MX1 Myxovirus (influenza virus) resistance 1, 1.98 NM_002462 351
    interferon-inducible protein p78 (mouse)
    PDLIM4 PDZ and LIM domain 4 1.977 NM_003687 352
    OAS2 2′-5′-oligoadenylate synthetase 2, 1.974 NM_016817 353
    69/71 kDa
    MKI67 Antigen identified by monoclonal antibody 1.971 NM_002417 354
    Ki-67
    RBPMS RNA binding protein with multiple splicing 1.971 NM_001008710 355
    PARP9 Poly (ADP-ribose) polymerase family, 1.968 NM_031458 356
    member 9
    ABCC5 ATP-binding cassette, sub-family C 1.961 NM_005688 357
    (CFTR/MRP), member 5
    CLDN1 Claudin 1 1.961 AV659222 358
    T3JAM TRAF3 interacting protein 3 1.958 NM_025228 359
    IKBKAP Inhibitor of kappa light polypeptide gene 1.955 NM_003640 360
    enhancer in B-cells, kinase complex-
    associated protein
    FAM46A Family with sequence similarity 46, 1.955 NM_017633 361
    member A
    CHST9 Carbohydrate (N-acetylgalactosamine 4- 1.954 NM_031422 362
    0) sulfotransferase 9
    KIAA1272 Chromosome 20 open reading frame 74 1.953 AY007156 363
    NIP Homolog of Drosophila Numb-interacting 1.953 NM_144565 364
    protein
    DRAP1 Similar to ankyrin 1.951 BC018095 365
    SART2 Squamous cell carcinoma antigen 1.951 NM_013352 366
    recognized by T cells 2
    SPBC25 Spindle pole body component 25 homolog 1.95 NM_020675 367
    (S. cerevisiae)
    NFATC2 Nuclear factor of activated T-cells, 1.949 NM_173091 368
    cytoplasmic, calcineurin-dependent 2
    SLC9A3 Solute carrier family 9 (sodium/hydrogen 1.948 AL137723 369
    exchanger), isoform 3
    SEQ_ID_#370 CDNA: FLJ23006 fis, clone LNG00414 1.948 AK026659 370
    C6orf173 Chromosome 6 open reading frame 173 1.946 NM_001012507 371
    CYP4X1 Cytochrome P450, family 4, subfamily X, 1.946 NM_178033 372
    polypeptide 1
    DUSP10 Dual specificity phosphatase 10 1.945 NM_007207 373
    PTPN6 Protein tyrosine phosphatase, non- 1.943 NM_002831 374
    receptor type 6
    FGF11 Fibroblast growth factor 11 1.94 NM_004112 375
    NFIL3 Nuclear factor, interleukin 3 regulated 1.939 NM_005384 376
    CMYA5 Cardiomyopathy associated 5 1.938 NM_153610 377
    MGC4677 Hypothetical protein MGC4677 1.938 NM_052871 378
    KCNE3 Potassium voltage-gated channel, Isk- 1.937 NM_005472 379
    related family, member 3
    WHSC1 Wolf-Hirschhorn syndrome candidate 1 1.936 BF509385 380
    NCF4 Neutrophil cytosolic factor 4, 40 kDa 1.935 NM_000631 381
    CD300LF CD300 antigen like family member F 1.934 NM_139018 382
    TMC6 Epidermodysplasia verruciformis 1 1.93 NM_007267 383
    AP1G2 Adaptor-related protein complex 1, 1.929 NM_003917 384
    gamma 2 subunit
    MGC4368 1.924 NM_001033046 385
    LOC441109 Hypothetical gene supported by 1.923 XM_499014 386
    AL713721
    LAPTM5 Lysosomal associated multispanning 1.923 NM_006762 387
    membrane protein 5
    SEQ_ID_#388 BX438987 Homo sapiens PLACENTA 1.921 BX438987 388
    Homo sapiens cDNA clone
    CS0DE005YG01 3-PRIME, mRNA
    sequence.
    ELF4 E74-like factor 4 (ets domain 1.92 NM_001421 389
    transcription factor)
    ARHGEF5 Rho guanine nucleotide exchange factor 1.919 NM_001002861 390
    (GEF) 5
    PRODH Proline dehydrogenase (oxidase) 1 1.913 NM_016335 391
    GALNAC4S-6ST B cell RAG associated protein 1.913 NM_015892 392
    MGC17791 Tumor necrosis factor, alpha-induced 1.912 NM_152362 393
    protein 8-like 1
    BIK BCL2-interacting killer (apoptosis- 1.911 NM_001197 394
    inducing)
    FAM54A Family with sequence similarity 54, 1.911 NM_138419 395
    member A
    VWA1 Von Willebrand factor A domain 1.91 NM_022834 396
    containing 1
    LOC401115 Hypothetical gene supported by 1.909 XM_379250 397
    BC038466; BC062790
    CD40 CD40 antigen (TNF receptor superfamily 1.907 NM_001250 398
    member 5)
    L3MBTL L(3)mbt-like (Drosophila) 1.907 NM_015478 399
    SAA2 Serum amyloid A2 1.907 NM_030754 400
    ECT2 Epithelial cell transforming sequence 2 1.907 NM_018098 401
    oncogene
    MOV10 Mov10, Moloney leukemia virus 10, 1.903 NM_020963 402
    homolog (mouse)
    FLJ21103 Hypothetical protein FLJ21103 1.903 NM_024556 403
    KLRK1 Killer cell lectin-like receptor subfamily K, 1.9 NM_007360 404
    member 1
    SEQ_ID_#405 CDNA FLJ44429 fis, clone UTERU2015653 1.9 AJ318805 405
    SCOTIN Scotin 1.899 NM_016479 406
    WDR51B WD repeat domain 51B 1.896 NM_172240 407
    FLT3LG Fms-related tyrosine kinase 3 ligand 1.896 NM_001459 408
    KIAA0493 KIAA0493 protein 1.89 AB007962 409
    LTA4H Leukotriene A4 hydrolase 1.888 NM_000895 410
    USP54 Ubiquitin specific protease 54 1.888 NM_152586 411
    TACC3 Transforming, acidic coiled-coil containing 1.888 NM_006342 412
    protein 3
    LGALS3BP Lectin, galactoside-binding, soluble, 3 1.888 NM_005567 413
    binding protein
    LOC440288 Similar to FLJ16518 protein 1.887 XM_496075 414
    G0S2 Putative lymphocyte G0/G1 switch gene 1.887 NM_015714 415
    CCBL1 Cysteine conjugate-beta lyase; 1.884 NM_004059 416
    cytoplasmic (glutamine transaminase K,
    kyneurenine aminotransferase)
    RGS19 Regulator of G-protein signalling 19 1.883 NM_005873 417
    KLHL5 Kelch-like 5 (Drosophila) 1.883 NM_001007075 418
    VILL Villin-like 1.883 NM_015873 419
    GLCCI1 Glucocorticoid induced transcript 1 1.881 NM_138426 420
    TYROBP TYRO protein tyrosine kinase binding 1.879 NM_003332 421
    protein
    CDC2 Cell division cycle 2, G1 to S and G2 to M 1.879 NM_001786 422
    LOC158402 Hypothetical protein LOC158402 1.878 AK095652 423
    PRSS12 Protease, serine, 12 (neurotrypsin, 1.878 NM_003619 424
    motopsin)
    SEQ_ID_#425 Transcribed locus 1.877 AI632517 425
    FAM20C Family with sequence similarity 20, 1.875 NM_020223 426
    member C
    GBP2 Guanylate binding protein 2, interferon- 1.868 NM_004120 427
    inducible
    SEQ_ID_#428 CDNA FLJ45384 fis, clone BRHIP3021987 1.866 AK127315 428
    HIST3H2A Histone 3, H2a 1.866 NM_033445 429
    OLFML2A Olfactomedin-like 2A 1.864 NM_182487 430
    TNFSF10 Tumor necrosis factor (ligand) 1.862 NM_003810 431
    superfamily, member 10
    LOC120376 Hypothetical protein LOC120376 1.858 XM_071712 432
    EPHA4 EPH receptor A4 1.858 NM_004438 433
    DERL2 Der1-like domain family, member 2 1.856 NM_016041 434
    CYP2R1 Cytochrome P450, family 2, subfamily R, 1.852 NM_024514 435
    polypeptide 1
    VSNL1 Visinin-like 1 1.85 NM_003385 436
    MGAT3 Mannosyl (beta-1,4-)-glycoprotein beta- 1.85 NM_002409 437
    1,4-N-acetylglucosaminyltransferase
    CLMN Calmin (calponin-like, transmembrane) 1.846 NM_024734 438
    HES2 Hairy and enhancer of split 2 (Drosophila) 1.841 NM_019089 439
    SEQ_ID_#440 LOC441069 1.84 AK056817 440
    DDX39 DEAD (Asp-Glu-Ala-Asp) box polypeptide 1.839 NM_005804 441
    39
    SEQ_ID_#442 Transcribed locus 1.839 AW979271 442
    PARP8 Poly (ADP-ribose) polymerase family, 1.838 NM_024615 443
    member 8
    CLN5 Ceroid-lipofuscinosis, neuronal 5 1.835 NM_006493 444
    HLA-B Major histocompatibility complex, class I, B 1.834 NM_005514 445
    RAB34 RAB34, member RAS oncogene family 1.834 NM_031934 446
    BTK Bruton agammaglobulinemia tyrosine 1.832 NM_000061 447
    kinase
    AMICA1 Adhesion molecule, interacts with CXADR 1.83 NM_153206 448
    antigen 1
    SEQ_ID_#449 Transcribed locus 1.83 BG771234 449
    SEQ_ID_#450 Transcribed locus, weakly similar to 1.829 BG483393 450
    XP_517655.1 PREDICTED: similar to
    KIAA0825 protein [Pan troglodytes]
    TNFRSF10B Tumor necrosis factor receptor 1.826 NM_003842 451
    superfamily, member 10b
    CEACAM1 Carcinoembryonic antigen-related cell 1.821 NM_001024912 452
    adhesion molecule 1 (biliary glycoprotein)
    EGFL6 EGF-like-domain, multiple 6 1.821 NM_015507 453
    VAMP5 Vesicle-associated membrane protein 5 1.82 NM_006634 454
    (myobrevin)
    FLT1 Fms-related tyrosine kinase 1 (vascular 1.82 NM_002019 455
    endothelial growth factor/vascular
    permeability factor receptor)
    SEQ_ID_#456 Transcribed locus, weakly similar to 1.819 BQ010718 456
    XP_498452.1 PREDICTED: hypothetical
    protein XP_498452 [Homo sapiens]
    GPR82 G protein-coupled receptor 82 1.819 BX438968 457
    UQCRC1 Ubiquinol-cytochrome c reductase core 1.818 NM_003365 458
    protein I
    RNASE1 Ribonuclease, RNase A family, 1 1.818 NM_002933 459
    (pancreatic)
    NOD27 Nucleotide-binding oligomerization 1.817 NM_032206 460
    domains 27
    PTPNS1 Protein tyrosine phosphatase, non- 1.817 NM_080792 461
    receptor type substrate 1
    3′HEXO Three prime histone mRNA exonuclease 1 1.817 NM_153332 462
    C3AR1 Complement component 3a receptor 1 1.815 NM_004054 463
    ITPR3 Inositol 1,4,5-triphosphate receptor, type 3 1.813 NM_002224 464
    LRRC8A Leucine rich repeat containing 8 family, 1.81 NM_019594 465
    member A
    ST8SIA6; SIAT8F; synonyms: SIAT8F, ST8SIA-VI, ST8Sia 1.81 XM_291725 466
    ST8SIA-VI; ST8Sia VI; sialyltransferase 8F; sialyltransferase
    VI 8F (alpha-2, 8-sialyltransferase);
    go_component: membrane [goid
    0016020] [evidence IEA];
    go_component: Golgi stack [goid
    0005795] [evidence IEA];
    go_component: integral to membrane
    [goid 0016021] [evidence IEA];
    go_function: sialyltransferase activity
    [goid 0008373] [evidence IEA];
    go_process: protein amino acid
    glycosylation [goid 0006486] [evidence
    IEA]; Homo sapiens ST8 alpha-N-acetyl-
    neuraminide alpha-2,8-sialyltransferase 6
    (ST8SIA6), mRNA.
    C17orf27 Chromosome 17 open reading frame 27 1.808 NM_020914 467
    FBXL18 F-box and leucine-rich repeat protein 18 1.808 NM_024963 468
    FOXQ1 Forkhead box Q1 1.807 NM_033260 469
    CXorf9 Chromosome X open reading frame 9 1.807 NM_018990 470
    TAPBPL TAP binding protein-like 1.805 NM_018009 471
    FAM50A Family with sequence similarity 50, 1.805 NM_004699 472
    member A
    GGA2 Golgi associated, gamma adaptin ear 1.805 NM_015044 473
    containing, ARF binding protein 2
    TLOC1 Translocation protein 1 1.802 NM_003262 474
    HLA-E Major histocompatibility complex, class I, E 1.801 NM_005516 475
    SEQ_ID_#476 Transcribed locus 1.8 BM999272 476
    TTMP TPA-induced transmembrane protein 1.798 NM_024616 477
    SEQ_ID_#479 CDNA FLJ39947 fis, clone SPLEN2024232 1.798 AK097266 478
    SLC39A8 Solute carrier family 39 (zinc 1.796 NM_022154 479
    transporter), member 8
    E2F2 E2F transcription factor 2 1.796 NM_004091 480
    NUP210 Nucleoporin 210 kDa 1.796 NM_024923 481
    PPAP2C Phosphatidic acid phosphatase type 2C 1.795 NM_003712 482
    EHMT2 Euchromatic histone-lysine N- 1.793 NM_006709 483
    methyltransferase 2
    RYR2 Ryanodine receptor 2 (cardiac) 1.793 NM_001035 484
    IL15RA Interleukin 15 receptor, alpha 1.793 NM_002189 485
    STK6 Serine/threonine kinase 6 1.793 NM_003600 486
    LAMB3 Laminin, beta 3 1.792 NM_000228 487
    SPTBN1 Spectrin, beta, non-erythrocytic 1 1.792 NM_003128 488
    ETV6 Ets variant gene 6 (TEL oncogene) 1.791 NM_001987 489
    PSMB7 Proteasome (prosome, macropain) 1.791 NM_002799 490
    subunit, beta type, 7
    HMGB3 synonyms: HMG4, HMG2A, MGC90319; 1.79 NM_005342 491
    high-mobility group (nonhistone
    chromosomal) protein 4; non-histone
    chromosomal protein; go_component:
    nucleus [goid 0005634] [evidence IEA];
    go_component: chromatin [goid
    0000785] [evidence IEA]; go_function:
    DNA binding [goid 0003677] [evidence
    IEA]; go_function: DNA bending activity
    [goid 0008301] [evidence TAS] [pmid
    9598312]; go_process: development
    [goid 0007275] [evidence TAS] [pmid
    9598312]; go_process: regulation of
    transcription, DNA-dependent [goid
    0006355] [evidence IEA]; Homo sapiens
    high-mobility group box 3 (HMGB3),
    mRNA.
    DOK3 Docking protein 3 1.79 NM_024872 492
    DNAPTP6 DNA polymerase-transactivated protein 6 1.787 NM_015535 493
    LOC285835 Hypothetical protein LOC285835 1.787 BC035656 494
    CDC20 CDC20 cell division cycle 20 homolog (S. cerevisiae) 1.781 NM_001255 495
    SEQ_ID_#496 AGENCOURT_7258511 NIH_MGC_71 1.781 BQ219651 496
    Homo sapiens cDNA clone
    IMAGE: 5786579 5′, mRNA sequence.
    TNFRSF10A Tumor necrosis factor receptor 1.78 NM_003844 497
    superfamily, member 10a
    KIF4A Kinesin family member 4A 1.779 NM_012310 498
    SEQ_ID_#499 UI-CF-FN0-afk-f-10-0-UI.s1 UI-CF-FN0 1.777 CA312567 499
    Homo sapiens cDNA clone UI-CF-FN0-afk-
    f-10-0-UI 3′, mRNA sequence.
    SDF2 Stromal cell-derived factor 2 1.776 NM_006923 500
    PCCA Propionyl Coenzyme A carboxylase, alpha 1.776 NM_000282 501
    polypeptide
    TM7SF1 Transmembrane 7 superfamily member 1 1.774 NM_003272 502
    (upregulated in kidney)
    DKFZP564K1964 1.773 NM_001033504 503
    VSIG4 V-set and immunoglobulin domain 1.771 NM_007268 504
    containing 4
    TNIP2 TNFAIP3 interacting protein 2 1.77 NM_024309 505
    KIAA0513 KIAA0513 1.768 NM_014732 506
    PPM1M Protein phosphatase 1M (PP2C domain 1.767 NM_144641 507
    containing)
    EXOC3 SEC6-like 1 (S. cerevisiae) 1.767 NM_007277 508
    PSME2 Proteasome (prosome, macropain) 1.767 NM_002818 509
    activator subunit 2 (PA28 beta)
    RAB7 RAB7, member RAS oncogene family 1.766 NM_004637 510
    SEQ_ID_#511 CDNA clone IMAGE: 6043059 1.764 BC039021 511
    TNFRSF14 Tumor necrosis factor receptor 1.763 NM_003820 512
    superfamily, member 14 (herpesvirus
    entry mediator)
    KRT4 Keratin 4 1.762 NM_002272 513
    CST3 Cystatin C (amyloid angiopathy and 1.761 NM_000099 514
    cerebral hemorrhage)
    MGC19764 Hypothetical protein MGC19764 1.756 NM_144975 515
    NUP50 Nucleoporin 50 kDa 1.756 NM_007172 516
    SFXN1 Sideroflexin 1 1.754 NM_022754 517
    BIRC5 Effector cell protease receptor 1 1.753 NM_001012270 518
    IL2RG Interleukin 2 receptor, gamma (severe 1.753 NM_000206 519
    combined immunodeficiency)
    RIPK2 Receptor-interacting serine-threonine 1.751 NM_003821 520
    kinase 2
    SEQ_ID_#521 Non-coding transcript, polyA signal, clone 1.75 BC040308 521
    44-5SB/3L
    RTKN Rhotekin 1.75 NM_001015055 522
    NDFIP2 Nedd4 family interacting protein 2 1.749 NM_019080 523
    ARRDC2 Arrestin domain containing 2 1.749 NM_001025604 524
    EFHD2 EF-hand domain family, member D2 1.747 NM_024329 525
    C9orf127 Chromosome 9 open reading frame 127 1.747 NM_016446 526
    KIAA1509 KIAA1509 1.747 XM_029353 527
    ACPL2 1.744 NM_001037172 528
    SEQ_ID_#529 LOC441069 1.742 AK056817 529
    FAM100B Hypothetical protein MGC29814 1.742 NM_182565 530
    BTG3 BTG family, member 3 1.741 NM_006806 531
    PITPNC1 Phosphatidylinositol transfer protein, 1.741 NM_012417 532
    cytoplasmic 1
    RAB40B RAB40B, member RAS oncogene family 1.74 NM_006822 533
    ICAM4 Intercellular adhesion molecule 4, 1.738 NM_001544 534
    Landsteiner-Wiener blood group
    FXYD3 FXYD domain containing ion transport 1.736 NM_005971 535
    regulator 3
    SPSB1 SPRY domain-containing SOCS box 1.735 NM_025106 536
    protein SSB-1
    GCH1 GTP cyclohydrolase 1 (dopa-responsive 1.734 NM_000161 537
    dystonia)
    SEQ_ID_#538 IL3-CT0674-060401-492-F11 CT0674 1.734 BG960486 538
    Homo sapiens cDNA, mRNA sequence.
    MELK Maternal embryonic leucine zipper kinase 1.731 NM_014791 539
    KIAA1404 KIAA1404 protein 1.731 NM_021035 540
    SYNPO Synaptopodin 1.73 NM_007286 541
    MAN2B1 Mannosidase, alpha, class 2B, member 1 1.729 NM_000528 542
    MAOA Monoamine oxidase A 1.729 NM_000240 543
    CCR3 Chemokine (C-C motif) receptor 3 1.729 NM_001837 544
    APBA3 Amyloid beta (A4) precursor protein- 1.727 NM_004886 545
    binding, family A, member 3 (X11-like 2)
    OASL 2′-5′-oligoadenylate synthetase-like 1.726 NM_003733 546
    PAFAH1B3 Platelet-activating factor acetylhydrolase, 1.726 NM_002573 547
    isoform Ib, gamma subunit 29 kDa
    ARHGAP18 Rho GTPase activating protein 18 1.725 NM_033515 548
    MGC13098 Hypothetical protein MGC13098 1.723 BX537878 549
    ARHGAP9 Rho GTPase activating protein 9 1.722 NM_032496 550
    INSIG1 Insulin induced gene 1 1.721 NM_005542 551
    ADORA3 Adenosine A3 receptor 1.72 NM_000677 552
    VWF Von Willebrand factor 1.717 NM_000552 553
    AGTRAP Angiotensin II receptor-associated protein 1.716 NM_020350 554
    ITGAE Integrin, alpha E (antigen CD103, human 1.715 NM_002208 555
    mucosal lymphocyte antigen 1; alpha
    polypeptide)
    SMAD1 SMAD, mothers against DPP homolog 1 1.715 NM_001003688 556
    (Drosophila)
    RHBDL7 Rhomboid, veinlet-like 7 (Drosophila) 1.713 NM_020684 557
    HLA-F Major histocompatibility complex, class I, F 1.713 NM_018950 558
    DTX3L Deltex 3-like (Drosophila) 1.711 NM_138287 559
    SDK1 Sidekick homolog 1 (chicken) 1.708 NM_152744 560
    LCK Lymphocyte-specific protein tyrosine 1.708 NM_005356 561
    kinase
    CBLC Cas-Br-M (murine) ecotropic retroviral 1.707 NM_012116 562
    transforming sequence c
    SEQ_ID_#563 601344760F1 NIH_MGC_8 Homo sapiens 1.706 BE562274 563
    cDNA clone IMAGE: 3677607 5′, mRNA
    sequence.
    CHST7 Carbohydrate (N-acetylglucosamine 6-O) 1.706 NM_019886 564
    sulfotransferase 7
    CDCA2 Cell division cycle associated 2 1.706 NM_152562 565
    ACOT9 1.706 NM_001033583 566
    TYMS Thymidylate synthetase 1.705 NM_001071 567
    HCA112 Hepatocellular carcinoma-associated 1.705 NM_018487 568
    antigen 112
    EVER2 Epidermodysplasia verruciformis 2 1.7 NM_152468 569
    LAYN Layilin 1.7 NM_178834 570
    MGC7036 Hypothetical protein MGC7036 1.699 NM_145058 571
    FLJ11029 Hypothetical protein FLJ11029 1.699 NM_018304 572
    FLJ10996 synonym: MGC13033; Homo sapiens 1.696 NM_031447 573
    hypothetical protein FLJ10996
    (FLJ10996), mRNA.
    SEQ_ID_#574 Transcribed locus 1.695 BQ010979 574
    CENPF Centromere protein F, 350/400ka 1.693 NM_016343 575
    (mitosin)
    BTN3A2 Butyrophilin, subfamily 3, member A2 1.692 NM_007047 576
    GAS2L3 Growth arrest-specific 2 like 3 1.692 NM_174942 577
    KRT19 Keratin 19 1.69 NM_002276 578
    HLA-C Major histocompatibility complex, class I, C 1.689 NM_002117 579
    ATP11A ATPase, Class VI, type 11A 1.688 NM_015205 580
    SEQ_ID_#581 Transcribed locus, weakly similar to 1.688 BI820139 581
    NP_009083.1 zinc finger protein 195
    [Homo sapiens ]
    SEMA4C Sema domain, immunoglobulin domain 1.688 NM_017789 582
    (Ig), transmembrane domain (TM) and
    short cytoplasmic domain, (semaphorin)
    4C
    CCNB1 Cyclin B1 1.685 NM_031966 583
    CLDN4 Claudin 4 1.684 NM_001305 584
    CCM2 Cerebral cavernous malformation 2 1.683 NM_001029835 585
    UBE2C Ubiquitin-conjugating enzyme E2C 1.682 NM_007019 586
    FAM3C Family with sequence similarity 3, 1.681 NM_014888 587
    member C
    SERTAD4 SERTA domain containing 4 1.681 NM_019605 588
    ELF3 E74-like factor 3 (ets domain 1.68 NM_004433 589
    transcription factor, epithelial-specific)
    FCGRT Fc fragment of IgG, receptor, transporter, 1.678 NM_004107 590
    alpha
    LOC55831 30 kDa protein 1.677 NM_018447 591
    APOBEC3C Apolipoprotein B mRNA editing enzyme, 1.676 NM_014508 592
    catalytic polypeptide-like 3C
    FAS Fas (TNF receptor superfamily, member 1.676 NM_000043 593
    6)
    RDH10 Retinol dehydrogenase 10 (all-trans) 1.675 NM_172037 594
    LOC440836 Endothelial cell growth factor 1 (platelet- 1.675 NM_001014440 595
    derived)
    TRIM47 Tripartite motif-containing 47 1.675 NM_033452 596
    SEQ_ID_#597 T-cell receptor V beta gene segment V- 1.674 BC035390 597
    beta-6, clone IGRb11
    SEQ_ID_#598 Transcribed locus 1.673 BX114460 598
    9-Sep Septin 9 1.672 NM_006640 599
    DHFR Dihydrofolate reductase 1.671 NM_000791 600
    SLC39A1 Solute carrier family 39 (zinc 1.67 NM_014437 601
    transporter), member 1
    ARHGAP21 Rho GTPase activating protein 21 1.669 NM_020824 602
    FBLN1 Fibulin 1 1.668 NM_001996 603
    FOXM1 Forkhead box M1 1.668 NM_021953 604
    MGC14289 Similar to RIKEN cDNA 1200014N16 gene 1.666 NM_080660 605
    SEQ_ID_#606 UI-E-EJ0-aik-f-24-0-UI.s1 UI-E-EJ0 Homo 1.666 BM681765 606
    sapiens cDNA clone UI-E-EJ0-aik-f-24-0-
    UI 3′, mRNA sequence.
    ROBO1 Roundabout, axon guidance receptor, 1.666 NM_002941 607
    homolog 1 (Drosophila)
    ADAM12 A disintegrin and metalloproteinase 1.665 NM_003474 608
    domain 12 (meltrin alpha)
    BDNF Brain-derived neurotrophic factor 1.664 NM_001709 609
    opposite strand
    RPS8 Ribosomal protein S8 1.663 NM_001012 610
    P2RY2 Purinergic receptor P2Y, G-protein 1.661 NM_002564 611
    coupled, 2
    C9orf55 Chromosome 9 open reading frame 55 1.661 NM_017925 612
    IKBKE Inhibitor of kappa light polypeptide gene 1.661 NM_014002 613
    enhancer in B-cells, kinase epsilon
    RARA Retinoic acid receptor, alpha 1.661 NM_000964 614
    ST6GALNAC2 ST6 (alpha-N-acetyl-neuraminyl-2,3- 1.66 NM_006456 615
    beta-galactosyl-1,3)-N-
    acetylgalactosaminide alpha-2,6-
    sialyltransferase 2
    NDUFS7 NADH dehydrogenase (ubiquinone) Fe—S 1.659 NM_024407 616
    protein 7, 20 kDa (NADH-coenzyme Q
    reductase)
    LAT Linker for activation of T cells 1.659 NM_001014987 617
    FLOT1 Flotillin 1 1.658 NM_005803 618
    MSMB Microseminoprotein, beta- 1.657 NM_002443 619
    TRIM11 Tripartite motif-containing 11 1.653 NM_145214 620
    SIPA1L1 Signal-induced proliferation-associated 1 1.653 NM_015556 621
    like 1
    TRAF4 TNF receptor-associated factor 4 1.652 NM_004295 622
    FLJ33860 RP5-1017F8.1; go_function: receptor 1.652 NM_173644 623
    activity [goid 0004872] [evidence IEA];
    Homo sapiens hypothetical protein
    FLJ33860 (FLJ33860), mRNA.
    WBSCR17 Williams-Beuren syndrome chromosome 1.651 NM_022479 624
    region 17
    RNASEH2A Ribonuclease H2, large subunit 1.65 NM_006397 625
    BPNT1 3′(2′),5′-bisphosphate nucleotidase 1 1.649 NM_006085 626
    CD3D CD3D antigen, delta polypeptide (TiT3 1.649 NM_000732 627
    complex)
    GBP5 Guanylate binding protein 5 1.647 NM_052942 628
    RNF19 Ring finger protein 19 1.646 NM_015435 629
    SEQ_ID_#630 Transcribed locus, moderately similar to 1.642 BF037662 630
    XP_508230.1 PREDICTED: zinc finger
    protein 195 [Pan troglodytes]
    DAPK2 Death-associated protein kinase 2 1.641 NM_014326 631
    CCNB2 Glutamate decarboxylase 1 (GAD 1) 1.641 NM_004701 632
    FNTB Farnesyltransferase, CAAX box, beta 1.64 NM_002028 633
    C16orf7 Chromosome 16 open reading frame 7 1.64 NM_004913 634
    NR4A2 Nuclear receptor subfamily 4, group A, 1.637 NM_006186 635
    member 2
    PITRM1 Pitrilysin metalloproteinase 1 1.636 NM_014889 636
    DOCK7 Dedicator of cytokinesis 7 1.636 BG546677 637
    JDP2 Jun dimerization protein 2 1.635 NM_130469 638
    SEQ_ID_#639 601344760F1 NIH_MGC_8 Homo sapiens 1.635 BE562274 639
    cDNA clone IMAGE: 3677607 5′, mRNA
    sequence.
    EAP30 EAP30 subunit of ELL complex 1.635 NM_007241 640
    DAF Decay accelerating factor for complement 1.634 NM_000574 641
    (CD55, Cromer blood group system)
    CUEDC2 CUE domain containing 2 1.633 NM_024040 642
    PLAU Plasminogen activator, urokinase 1.633 NM_002658 643
    HDAC9 Histone deacetylase 9 1.632 NM_014707 644
    PTCH Patched homolog (Drosophila) 1.632 NM_000264 645
    TNFRSF25 Tumor necrosis factor receptor 1.631 NM_003790 646
    superfamily, member 25
    TK1 Thymidine kinase 1, soluble 1.628 NM_003258 647
    FLJ11286 Hypothetical protein FLJ11286 1.628 NM_018381 648
    CDCA5 Cell division cycle associated 5 1.628 NM_080668 649
    SEMA3B Sema domain, immunoglobulin domain 1.627 NM_004636 650
    (Ig), short basic domain, secreted,
    (semaphorin) 3B
    PCSK6 Proprotein convertase subtilisin/kexin 1.627 NM_002570 651
    type 6
    C8orf72 Hypothetical protein MGC39325 1.626 NM_147189 652
    STARD5 START domain containing 5 1.626 NM_030574 653
    JUB Jub, ajuba homolog (Xenopus laevis) 1.625 NM_032876 654
    NAPE-PLD N-acyl-phosphatidylethanolamine- 1.625 NM_198990 655
    hydrolyzing phospholipase D
    HIGD2A Hypothetical protein MGC2198 1.625 NM_138820 656
    C1RL Complement component 1, r 1.624 NM_016546 657
    subcomponent-like
    DKFZP564I0422 Hypothetical protein DKFZp564I0422 1.622 NM_031435 658
    SCCPDH Saccharopine dehydrogenase (putative) 1.62 NM_016002 659
    ZNF503 Zinc finger protein 503 1.616 AK024492 660
    PLEKHG3 Pleckstrin homology domain containing, 1.615 AB011171 661
    family G (with RhoGef domain) member 3
    CD209 CD209 antigen 1.615 NM_021155 662
    HLA-A Major histocompatibility complex, class I, A 1.614 NM_002116 663
    Cep290 Centrosome protein cep290 1.614 NM_025114 664
    KIAA1434 Hypothetical protein KIAA1434 1.612 NM_019593 665
    SEQ_ID_#666 Hypothetical LOC389188 1.612 AK097068 666
    SEQ_ID_#667 Hypothetical gene supported by 1.612 BX648423 667
    AL713721
    ARHGAP25 Rho GTPase activating protein 25 1.611 NM_001007231 668
    TEP1 Telomerase-associated protein 1 1.61 NM_007110 669
    HSC20 J-type co-chaperone HSC20 1.61 NM_172002 670
    DLG5 Discs, large homolog 5 (Drosophila) 1.61 NM_004747 671
    H6PD Hexose-6-phosphate dehydrogenase 1.61 NM_004285 672
    (glucose 1-dehydrogenase)
    OSBPL3 Oxysterol binding protein-like 3 1.609 NM_015550 673
    CDCP1 CUB domain containing protein 1 1.608 NM_022842 674
    RCN1 Reticulocalbin 1, EF-hand calcium binding 1.608 NM_002901 675
    domain
    BCL6 B-cell CLL/lymphoma 6 (zinc finger 1.608 NM_001706 676
    protein 51)
    MGAT4B Mannosyl (alpha-1,3-)-glycoprotein beta- 1.607 NM_014275 677
    1,4-N-acetylglucosaminyltransferase,
    isoenzyme B
    DPEP2 Dipeptidase 2 1.606 NM_022355 678
    CLNS1A Chloride channel, nucleotide-sensitive, 1A 1.605 NM_001293 679
    DEPDC1 DEP domain containing 1 1.605 NM_017779 680
    C10orf54 Cadherin-like 23 1.602 NM_022153 681
    SMC2L1 SMC2 structural maintenance of 1.602 NM_006444 682
    chromosomes 2-like 1 (yeast)
    ATG4D APG4 autophagy 4 homolog D (S. cerevisiae) 1.601 NM_032885 683
    FAM3B Family with sequence similarity 3, 1.601 NM_058186 684
    member B
    TRADD TNFRSF1A-associated via death domain 1.601 NM_003789 685
    GABARAPL1 GABA(A) receptor-associated protein like 1 1.6 NM_031412 686
    TGFBI Transforming growth factor, beta- 1.599 NM_000358 687
    induced, 68 kDa
    DAG1 Dystroglycan 1 (dystrophin-associated 1.599 NM_004393 688
    glycoprotein 1)
    TBC1D1 TBC1 (tre-2/USP6, BUB2, cdc16) domain 1.599 NM_015173 689
    family, member 1
    TCF4 Transcription factor 4 1.597 NM_003199 690
    PLXNA1 Plexin A1 1.597 NM_032242 691
    CKS2 CDC28 protein kinase regulatory subunit 2 1.597 NM_001827 692
    KIAA1295 KIAA1295 1.594 NM_001017995 693
    LOC144501 Hypothetical protein LOC144501 1.594 NM_182507 694
    MIR16 Membrane interacting protein of RGS16 1.593 NM_016641 695
    C7orf19 synonyms: CBCIP2, FLJ12474, FLJ14733; 1.592 NM_025156 696
    H_NH0514P08.8; CAP-binding protein
    complex interacting protein 2; Homo
    sapiens chromosome 7 open reading
    frame 19 (C7orf19), mRNA.
    SLC24A6 Solute carrier family 24 1.592 NM_024959 697
    (sodium/potassium/calcium exchanger),
    member 6
    ATP5G2 ATP synthase, H+ transporting, 1.592 NM_001002031 698
    mitochondrial F0 complex, subunit c
    (subunit 9), isoform 2
    AMOTL1 Angiomotin like 1 1.59 NM_130847 699
    EPAS1 Endothelial PAS domain protein 1 1.59 AK023572 700
    ADAM9 A disintegrin and metalloproteinase 1.587 NM_001005845 701
    domain 9 (meltrin gamma)
    HCK Hemopoietic cell kinase 1.586 NM_002110 702
    ACOX1 Acyl-Coenzyme A oxidase 1, palmitoyl 1.585 NM_004035 703
    SLC25A28 Solute carrier family 25, member 28 1.585 NM_031212 704
    DEF6 Differentially expressed in FDCP 6 1.585 NM_022047 705
    homolog (mouse)
    MYH9 Myosin, heavy polypeptide 9, non-muscle 1.584 NM_002473 706
    CD300A CD300A antigen 1.584 NM_007261 707
    CORO1A Coronin, actin binding protein, 1A 1.583 NM_007074 708
    RPS6KA1 Ribosomal protein S6 kinase, 90 kDa, 1.583 NM_001006665 709
    polypeptide 1
    TRAFD1 TRAF-type zinc finger domain containing 1 1.582 NM_006700 710
    NFE2L1 Nuclear factor (erythroid-derived 2)-like 1 1.582 NM_003204 711
    SLC35B2 Solute carrier family 35, member B2 1.581 NM_178148 712
    ETV7 Ets variant gene 7 (TEL2 oncogene) 1.581 NM_016135 713
    KIF2C Kinesin family member 2C 1.58 NM_006845 714
    KIAA0999 KIAA0999 protein 1.579 NM_025164 715
    NCOA7 Nuclear receptor coactivator 7 1.577 NM_181782 716
    IFI16 Interferon, gamma-inducible protein 16 1.577 NM_005531 717
    SEQ_ID_#718 AGENCOURT_10444615 NIH_MGC_82 1.576 BU852798 718
    Homo sapiens cDNA clone
    IMAGE: 6619338 5′, mRNA sequence.
    DTNBP1 Dystrobrevin binding protein 1 1.575 NM_032122 719
    CD9 CD9 antigen (p24) 1.574 AK025016 720
    AP4B1 Adaptor-related protein complex 4, beta 1 1.574 NM_006594 721
    subunit
    SLC25A23 Solute carrier family 25 (mitochondrial 1.574 NM_024103 722
    carrier; phosphate carrier), member 23
    CENTD2 Centaurin, delta 2 1.573 NM_015242 723
    ATAD2 ATPase family, AAA domain containing 2 1.573 NM_014109 724
    SEQ_ID_#725 CDNA FLJ38412 fis, clone FEBRA2009385 1.573 AK095731 725
    CIB1 Calcium and integrin binding 1 (calmyrin) 1.573 NM_006384 726
    C1orf93 Chromosome 1 open reading frame 93 1.568 NM_152371 727
    SEQ_ID_#728 602281279F1 NIH_MGC_86 Homo 1.568 BG109249 728
    sapiens cDNA clone IMAGE: 4368955 5′,
    mRNA sequence.
    SITPEC Signaling intermediate in Toll pathway, 1.567 NM_016581 729
    evolutionarily conserved
    GUSB Glucuronidase, beta 1.566 NM_000181 730
    FLJ10260 Hypothetical protein FLJ10260 1.565 NM_018042 731
    FSHPRH1 FSH primary response (LRPR1 homolog, 1.565 NM_006733 732
    rat) 1
    AURKB Aurora kinase B 1.564 NM_004217 733
    USP18 Ubiquitin specific protease 18 1.564 NM_017414 734
    PCDH9 Protocadherin 9 1.564 BC008476 735
    SFXN3 Sideroflexin 3 1.563 NM_030971 736
    TFEB Transcription factor EB 1.562 NM_007162 737
    BRRN1 Barren homolog (Drosophila) 1.561 NM_015341 738
    HFE Hemochromatosis 1.56 NM_000410 739
    NDUFB10 NADH dehydrogenase (ubiquinone) 1 1.56 NM_004548 740
    beta subcomplex, 10, 22 kDa
    FER1L3 Fer-1-like 3, myoferlin (C. elegans) 1.559 NM_013451 741
    ATP11C ATPase, Class VI, type 11C 1.559 NM_001010986 742
    LOC128387 TatD DNase domain containing 3 1.557 XM_375838 743
    MGC11242 Hypothetical protein MGC11242 1.556 NM_024320 744
    NUDT1 Nudix (nucleoside diphosphate linked 1.556 NM_002452 745
    moiety X)-type motif 1
    BTG1 B-cell translocation gene 1, anti- 1.556 NM_001731 746
    proliferative
    RBMS2 RNA binding motif, single stranded 1.555 NM_002898 747
    interacting protein 2
    C9orf91 Chromosome 9 open reading frame 91 1.554 NM_153045 748
    C20orf116 Chromosome 20 open reading frame 116 1.553 NM_023935 749
    GSDMDC1 Gasdermin domain containing 1 1.553 NM_024736 750
    AYTL2 Hypothetical protein FLJ12443 1.552 NM_024830 751
    PVRL2 Poliovirus receptor-related 2 (herpesvirus 1.552 NM_002856 752
    entry mediator B)
    DCP2 DCP2 decapping enzyme homolog (S. cerevisiae) 1.55 NM_152624 753
    SAV1 Salvador homolog 1 (Drosophila) 1.55 NM_021818 754
    CANT1 Calcium activated nucleotidase 1 1.55 NM_138793 755
    PLEKHG2 Pleckstrin homology domain containing, 1.549 NM_022835 756
    family G (with RhoGef domain) member 2
    IRF6 Interferon regulatory factor 6 1.548 NM_006147 757
    PDE4D Phosphodiesterase 4D, cAMP-specific 1.547 NM_006203 758
    (phosphodiesterase E3 dunce homolog,
    Drosophila)
    SEQ_ID_#759 1.547 XM_087056 759
    KLK10 Kallikrein 10 1.546 NM_002776 760
    GSR Glutathione reductase 1.545 NM_000637 761
    SEQ_ID_#762 Transcribed locus, moderately similar to 1.543 BX108121 762
    XP_498467.1 PREDICTED: hypothetical
    protein XP_498467 [Homo sapiens ]
    CDC45L CDC45 cell division cycle 45-like (S. cerevisiae) 1.543 NM_003504 763
    IGSF2 Immunoglobulin superfamily, member 2 1.543 NM_004258 764
    MYO1F Myosin IF 1.542 NM_012335 765
    ZFYVE16 Zinc finger, FYVE domain containing 16 1.542 NM_014733 766
    RAB31 RAB31, member RAS oncogene family 1.541 NM_006868 767
    TOMM34 Translocase of outer mitochondrial 1.54 NM_006809 768
    membrane 34
    SEQ_ID_#769 602977386F1 NIH_MGC_12 Homo 1.539 BI255338 769
    sapiens cDNA clone IMAGE: 5122341 5′,
    mRNA sequence.
    SEQ_ID_#770 Homo sapiens clone IMAGE: 110987 1.538 AF143866 770
    mRNA sequence.
    KIAA1305 KIAA1305 1.536 XM_370756 771
    HIP1R Huntingtin interacting protein-1-related 1.536 NM_003959 772
    PRKD2 Protein kinase D2 1.536 NM_016457 773
    ACP2 Acid phosphatase 2, lysosomal 1.534 NM_001610 774
    COPZ2 Coatomer protein complex, subunit zeta 2 1.533 NM_016429 775
    GNG10 DnaJ-like protein 1.533 NM_004125 776
    SEQ_ID_#777 Transcribed locus 1.533 BX117393 777
    C1orf85 Chromosome 1 open reading frame 85 1.532 NM_144580 778
    NTF5 Neurotrophin 5 (neurotrophin 4/5) 1.532 NM_006179 779
    KIAA0101 synonyms: L5, NS5ATP9; isoform 2 is 1.531 NM_001029989 780
    encoded by transcript variant 2; Homo
    sapiens KIAA0101 (KIAA0101), transcript
    variant 2, mRNA.
    CLOCK Clock homolog (mouse) 1.531 NM_004898 781
    SEQ_ID_#782 AGENCOURT_10424058 NIH_MGC_79 1.53 BU929651 782
    Homo sapiens cDNA clone
    IMAGE: 6663644 5′, mRNA sequence.
    SEQ_ID_#783 601488213F1 NIH_MGC_69 Homo 1.53 BE876649 783
    sapiens cDNA clone IMAGE: 3890762 5′,
    mRNA sequence.
    KCTD7 Potassium channel tetramerisation 1.529 NM_153033 784
    domain containing 7
    RANGNRF RAN guanine nucleotide release factor 1.528 NM_016492 785
    KIAA1505 KIAA1505 protein 1.528 NM_020879 786
    SEQ_ID_#787 UI-H-BI4-apu-h-06-0-UI.s1 1.528 BF512055 787
    NCI_CGAP_Sub8 Homo sapiens cDNA
    clone IMAGE: 3088762 3′, mRNA
    sequence.
    MARVELD3 MARVEL domain containing 3 1.528 NM_052858 788
    MYOC Myocilin, trabecular meshwork inducible 1.528 BM712946 789
    glucocorticoid response
    CCND3 Cyclin D3 1.526 NM_001760 790
    NAT1 N-acetyltransferase 1 (arylamine N- 1.524 NM_000662 791
    acetyltransferase)
    CD97 CD97 antigen 1.524 NM_001025160 792
    OCIAD2 OCIA domain containing 2 1.522 NM_001014446 793
    PKIA Protein kinase (cAMP-dependent, 1.522 NM_006823 794
    catalytic) inhibitor alpha
    C2 Complement component 2 1.521 NM_000063 795
    ACD Adrenocortical dysplasia homolog 1.521 NM_022914 796
    (mouse)
    FAM83E Hypothetical protein FLJ20200 1.521 NM_017708 797
    S100P S100 calcium binding protein P 1.52 NM_005980 798
    COX5B Cytochrome c oxidase subunit Vb 1.52 NM_001862 799
    CCR1 Chemokine (C-C motif) receptor 1 1.52 NM_001295 800
    SLC35D2 Solute carrier family 35, member D2 1.518 NM_007001 801
    THAP4 THAP domain containing 4 1.518 NM_015963 802
    CHEK1 CHK1 checkpoint homolog (S. pombe) 1.517 NM_001274 803
    ZNF326 Zinc finger protein 326 1.516 NM_181781 804
    HDHD1A Haloacid dehalogenase-like hydrolase 1.515 NM_012080 805
    domain containing 1A
    SEQ_ID_#806 CDNA FLJ31593 fis, clone NT2RI2002481 1.514 AK056155 806
    SEQ_ID_#807 UI-H-CO0-asu-e-10-0-UI.s1 1.514 BM988141 807
    NCI_CGAP_Sub9 Homo sapiens cDNA
    clone IMAGE: 5859954 3′, mRNA
    sequence.
    SEQ_ID_#808 Transcribed locus 1.513 BM994952 808
    WARP Von Willebrand factor A domain 1.513 NM_022834 809
    containing 1
    FLJ22794 FLJ22794 protein 1.513 NM_022074 810
    STAT2 Signal transducer and activator of 1.512 NM_005419 811
    transcription 2, 113 kDa
    SEQ_ID_#812 Homo sapiens, clone IMAGE: 5092955 1.512 BC046188 812
    ANKRD10 Ankyrin repeat domain 10 1.512 NM_017664 813
    SLC25A29 Solute carrier family 25, member 29 1.511 NM_152333 814
    SSBP2 Single-stranded DNA binding protein 2 1.51 BQ027821 815
    BCL11B B-cell CLL/lymphoma 11B (zinc finger 1.509 NM_022898 816
    protein)
    ADAR Adenosine deaminase, RNA-specific 1.509 NM_001025107 817
    HPCAL1 Hippocalcin-like 1 1.509 NM_002149 818
    PDPN Podoplanin 1.509 NM_001006624 819
    TAL1 T-cell acute lymphocytic leukemia 1 1.508 NM_003189 820
    JAK3 Janus kinase 3 (a protein tyrosine kinase, 1.508 NM_000215 821
    leukocyte)
    ITPK1 Inositol 1,3,4-triphosphate 5/6 kinase 1.508 NM_014216 822
    SCYL2 SCY1-like 2 (S. cerevisiae) 1.507 NM_017988 823
    BACE2 Beta-site APP-cleaving enzyme 2 1.507 NM_012105 824
    LOC203069 Hypothetical protein LOC203069 1.505 XM_114618 825
    LOC116238 Hypothetical protein BC014072 1.504 NM_138463 826
    MGC4093 Hypothetical protein MGC4093 1.504 NM_030578 827
    MGC17624 MGC17624 protein 1.504 BE872965 828
    RFX5 Regulatory factor X, 5 (influences HLA 1.503 NM_000449 829
    class II expression)
    GBF1 Golgi-specific brefeldin A resistance factor 1 1.503 NM_004193 830
    CPA6 Carboxypeptidase A6 1.502 NM_020361 831
    UCK2 Uridine-cytidine kinase 2 1.502 NM_012474 832
    PDXK Pyridoxal (pyridoxine, vitamin B6) kinase 1.501 NM_003681 833
    PLSCR3 Phospholipid scramblase 3 1.501 NM_020360 834
    SFRS5 Splicing factor, arginine/serine-rich 5 0.666 NM_006925 835
    LOC115294 Similar to hypothetical protein FLJ10883 0.665 NM_052937 836
    PALLD Palladin 0.665 NM_016081 837
    EPS8L1 EPS8-like 1 0.665 NM_017729 838
    STXBP6 Syntaxin binding protein 6 (amisyn) 0.665 NM_014178 839
    SEQ_ID_#840 Full length insert cDNA YI37C01 0.665 BU737911 840
    ADIPOR1 Adiponectin receptor 1 0.664 NM_015999 841
    GNL3 Guanine nucleotide binding protein-like 3 0.664 NM_014366 842
    (nucleolar)
    C6orf69 Chromosome 6 open reading frame 69 0.663 NM_173562 843
    C15orf17 Chromosome 15 open reading frame 17 0.663 NM_020447 844
    MGLL Monoglyceride lipase 0.663 AW298662 845
    NCE2 NEDD8-conjugating enzyme 0.662 NM_080678 846
    PRKCE Protein kinase C, epsilon 0.662 NM_005400 847
    SLCO4A1 Solute carrier organic anion transporter 0.662 BC025345 848
    family, member 4A1
    TTC9 Tetratricopeptide repeat domain 9 0.661 XM_027236 849
    GCSH Glycine cleavage system protein H 0.661 NM_004483 850
    (aminomethyl carrier)
    KPNA4 Karyopherin alpha 4 (importin alpha 3) 0.661 NM_002268 851
    GALNT14 UDP-N-acetyl-alpha-D- 0.66 NM_024572 852
    galactosamine:polypeptide N-
    acetylgalactosaminyltransferase 14
    (GalNAc-T14)
    PHF16 PHD finger protein 16 0.659 NM_014735 853
    TMEM65 Hypothetical protein BC017881 0.658 NM_194291 854
    SRPK1 SFRS protein kinase 1 0.656 NM_003137 855
    CPNE3 Copine III 0.656 NM_003909 856
    RPL18A Ribosomal protein L18a 0.656 NM_000980 857
    ZNF253 Zinc finger protein 253 0.656 NM_021047 858
    SPATA5L1 Spermatogenesis associated 5-like 1 0.656 NM_024063 859
    SF3B3 Splicing factor 3b, subunit 3, 130 kDa 0.655 NM_012426 860
    PFN1 Profilin 1 0.655 NM_005022 861
    ODZ4 Odz, odd Oz/ten-m homolog 4 0.654 XM_166254 862
    (Drosophila)
    MOSC1 MOCO sulphurase C-terminal domain 0.653 NM_022746 863
    containing 1
    LOC400027 Hypothetical gene supported by 0.653 BC047417 864
    BC047417
    BRAF V-raf murine sarcoma viral oncogene 0.653 NM_004333 865
    homolog B1
    CEBPG CCAAT/enhancer binding protein (C/EBP), 0.653 NM_001806 866
    gamma
    JMJD1C Jumonji domain containing 1C 0.653 NM_004241 867
    MAFF V-maf musculoaponeurotic fibrosarcoma 0.653 NM_012323 868
    oncogene homolog F (avian)
    FEM1C Fem-1 homolog c (C. elegans) 0.653 NM_020177 869
    EP300 E1A binding protein p300 0.652 BC040700 870
    ZNF505 Zinc finger protein 505 0.652 NM_031218 871
    KIAA1001 Arylsulfatase G 0.652 NM_014960 872
    SMAP1 Stromal membrane-associated protein 1 0.652 NM_021940 873
    C20orf161 Chromosome 20 open reading frame 161 0.652 NM_033421 874
    FLJ10726 Hypothetical protein FLJ10726 0.652 NM_018195 875
    MGC52423 Hypothetical protein MGC52423 0.652 NM_182517 876
    FLJ10156 Family with sequence similarity 64, 0.651 NM_019013 877
    member A
    RECQL5 RecQ protein-like 5 0.651 NM_004259 878
    DUSP16 Dual specificity phosphatase 16 0.651 NM_030640 879
    SLC7A11 Solute carrier family 7, (cationic amino 0.651 NM_014331 880
    acid transporter, y+ system) member 11
    HMGCS1 3-hydroxy-3-methylglutaryl-Coenzyme A 0.65 NM_002130 881
    synthase 1 (soluble)
    PPP2R2C Protein phosphatase 2 (formerly 2A), 0.65 NM_020416 882
    regulatory subunit B (PR 52), gamma
    isoform
    CYB561 Cytochrome b-561 0.649 NM_001017916 883
    CDK5R1 Cyclin-dependent kinase 5, regulatory 0.648 NM_003885 884
    subunit 1 (p35)
    MRC2 Mannose receptor, C type 2 0.648 NM_006039 885
    TUBB6 Tubulin, beta 6 0.648 NM_032525 886
    TNFRSF11A Tumor necrosis factor receptor 0.647 NM_003839 887
    superfamily, member 11a, NFKB activator
    SEC24C SEC24 related gene family, member C (S. cerevisiae) 0.647 NM_004922 888
    EIF4EBP2 Eukaryotic translation initiation factor 4E 0.646 NM_004096 889
    binding protein 2
    CPT1A Carnitine palmitoyltransferase 1A (liver) 0.646 NM_001876 890
    OXSR1 Oxidative-stress responsive 1 0.646 NM_005109 891
    NPEPPS Aminopeptidase puromycin sensitive 0.646 NM_006310 892
    BTBD7 BTB (POZ) domain containing 7 0.645 NM_018167 893
    EXTL2 0.645 NM_001033025 894
    LOC401152 HCV F-transactivated protein 1 0.645 NM_001001701 895
    MAP4K4 Mitogen-activated protein kinase kinase 0.644 NM_004834 896
    kinase kinase 4
    PCDH21 Protocadherin 21 0.644 NM_033100 897
    EYA3 Eyes absent homolog 3 (Drosophila) 0.644 NM_001990 898
    GRHL1 Grainyhead-like 1 (Drosophila) 0.644 NM_014552 899
    SORT1 Sortilin 1 0.643 NM_002959 900
    SEQ_ID_#901 602540462F1 NIH_MGC_59 Homo 0.643 BG495068 901
    sapiens cDNA clone IMAGE: 4671519 5′,
    mRNA sequence.
    MALL BENE protein 0.643 NM_005434 902
    WWTR1 WW domain containing transcription 0.641 NM_015472 903
    regulator 1
    MAPK14 Mitogen-activated protein kinase 14 0.641 NM_001315 904
    KIAA1128 KIAA1128 0.641 NM_018999 905
    SEQ_ID_#906 Clone IMAGE: 1257951, mRNA sequence 0.64 BM664056 906
    MAP3K9 Mitogen-activated protein kinase kinase 0.64 AK123430 907
    kinase 9
    MLLT4 Myeloid/lymphoid or mixed-lineage 0.64 NM_005936 908
    leukemia (trithorax homolog,
    Drosophila); translocated to, 4
    SEQ_ID_#909 Similar to ankyrin repeat domain 20A 0.639 BC016022 909
    KIAA0892; synonym: MGC75361; go_function: 0.638 XM_048457 910
    MGC75361 binding [goid 0005488] [evidence IEA];
    Homo sapiens KIAA0892 (KIAA0892),
    mRNA.
    MFSD1 Major facilitator superfamily domain 0.638 NM_022736 911
    containing 1
    CPEB2 Cytoplasmic polyadenylation element 0.638 NM_182485 912
    binding protein 2
    FOSL2 FOS-like antigen 2 0.638 NM_005253 913
    NFIB Nuclear factor I/B 0.638 NM_005596 914
    SEQ_ID_#915 602068385F1 NIH_MGC_58 Homo 0.638 BF542107 915
    sapiens cDNA clone IMAGE: 4067421 5′,
    mRNA sequence.
    CREG1 Cellular repressor of E1A-stimulated 0.637 NM_003851 916
    genes 1
    SEQ_ID_#917 Clone IMAGE: 110436 mRNA sequence 0.637 BU622887 917
    TMED10 Transmembrane trafficking protein 0.637 NM_006827 918
    KIAA0182 KIAA0182 protein 0.637 NM_014615 919
    P53AIP1 P53-regulated apoptosis-inducing protein 1 0.637 NM_022112 920
    FTHP1 Ferritin, heavy polypeptide pseudogene 1 0.636 J04755 921
    SLC6A15 Solute carrier family 6, member 15 0.635 NM_182767 922
    GCKR Glucokinase (hexokinase 4) regulator 0.634 NM_001486 923
    SAMD9 Sterile alpha motif domain containing 9 0.634 NM_017654 924
    C2orf4 Chromosome 2 open reading frame 4 0.634 NM_015955 925
    FLJ10826 0.633 NM_001031707 926
    FLJ25952 Zinc finger, DHHC-type containing 20 0.633 NM_153251 927
    RFFL Rififylin 0.633 NM_001017368 928
    BAIAP2L1 BAI1-associated protein 2-like 1 0.633 NM_018842 929
    LOC286052 Homo sapiens cDNA FLJ37785 fis, clone 0.632 AK095104 930
    BRHIP2028330.
    ANKRD15 Ankyrin repeat domain 15 0.632 NM_015158 931
    KA36 Type I hair keratin KA36 0.632 NM_182497 932
    CKAP4 Cytoskeleton-associated protein 4 0.632 NM_006825 933
    13CDNA73 Hypothetical protein CG003 0.632 NM_023037 934
    EPS15L1 Epidermal growth factor receptor pathway 0.632 NM_021235 935
    substrate 15-like 1
    CYP2C9 Cytochrome P450, family 2, subfamily C, 0.632 NM_000771 936
    polypeptide 9
    ADAMTS17 A disintegrin-like and metalloprotease 0.631 AK057529 937
    (reprolysin type) with thrombospondin
    type
    1 motif, 17
    SCEL Sciellin 0.631 NM_003843 938
    PDK1 Pyruvate dehydrogenase kinase, 0.631 NM_002610 939
    isoenzyme 1
    FBXL10 F-box and leucine-rich repeat protein 10 0.631 NM_001005366 940
    ZNF539 Zinc finger protein 254 0.631 NM_203282 941
    CES1 Carboxylesterase 1 0.631 NM_016280 942
    (monocyte/macrophage serine esterase
    1)
    SEQ_ID_#943 Homo sapiens cDNA FLJ36869 fis, clone 0.631 AK094188 943
    ASTRO2016819.
    HOOK1 Hook homolog 1 (Drosophila) 0.63 NM_015888 944
    CLCN3 Chloride channel 3 0.63 NM_001829 945
    SGPL1 Sphingosine-1-phosphate lyase 1 0.63 NM_003901 946
    CXCL14 Chemokine (C—X—C motif) ligand 14 0.629 NM_004887 947
    SEQ_ID_#948 CDNA FLJ20486 fis, clone KAT08039 0.629 AK000493 948
    DIO2 Deiodinase, iodothyronine, type II 0.629 NM_000793 949
    PRLR Prolactin receptor 0.628 NM_000949 950
    RANBP9 RAN binding protein 9 0.628 NM_005493 951
    TSPAN12 Tetraspanin 12 0.628 NM_012338 952
    SEQ_ID_#953 Transcribed locus, weakly similar to 0.627 BM987621 953
    XP_428540.1 PREDICTED: similar to
    putative 40S ribosomal protein 20S
    protein, partial [Gallus gallus ]
    LOC286170 Hypothetical protein LOC286170 0.627 AK055620 954
    C3orf4 Chromosome 3 open reading frame 4 0.627 NM_019895 955
    QSCN6 Quiescin Q6 0.627 NM_002826 956
    KCTD6 Potassium channel tetramerisation 0.627 NM_153331 957
    domain containing 6
    MAPT Microtubule-associated protein tau 0.626 NM_005910 958
    MAP1LC3A Microtubule-associated protein 1 light 0.625 NM_032514 959
    chain 3 alpha
    IFRD1 Interferon-related developmental 0.625 NM_001007245 960
    regulator 1
    ARHGEF4 Rho guanine nucleotide exchange factor 0.625 NM_015320 961
    (GEF) 4
    TIGA1 TIGA1 0.624 NM_053000 962
    ZBTB5 Zinc finger and BTB domain containing 5 0.624 NM_014872 963
    C20orf22 Chromosome 20 open reading frame 22 0.624 NM_015600 964
    LOC400451 Hypothetical gene supported by 0.623 NM_207446 965
    AK075564; BC060873
    PTPN21 Protein tyrosine phosphatase, non- 0.622 NM_007039 966
    receptor type 21
    SH3BP5 SH3-domain binding protein 5 (BTK- 0.622 NM_001018009 967
    associated)
    FLJ32028 Hypothetical protein FLJ32028 0.622 NM_152680 968
    ABCC1 ATP-binding cassette, sub-family C 0.622 NM_004996 969
    (CFTR/MRP), member 1
    LOC196264 Hypothetical protein LOC196264 0.621 NM_198275 970
    BSPRY B-box and SPRY domain containing 0.621 NM_017688 971
    PRDM1 PR domain containing 1, with ZNF domain 0.621 NM_001198 972
    GAS7 Growth arrest-specific 7 0.621 NM_003644 973
    TAX1BP1 Tax1 (human T-cell leukemia virus type I) 0.621 NM_006024 974
    binding protein 1
    HIPK3 Homeodomain interacting protein kinase 3 0.621 NM_005734 975
    TUBA1 Tubulin, alpha 1 (testis specific) 0.621 NM_006000 976
    PIGN Phosphatidylinositol glycan, class N 0.62 NM_012327 977
    SEQ_ID_#978 CDNA: FLJ22256 fis, clone HRC02860 0.62 AK025909 978
    SERPINB1 Serine (or cysteine) proteinase inhibitor, 0.62 NM_030666 979
    clade B (ovalbumin), member 1
    BCL2L10 BCL2-like 10 (apoptosis facilitator) 0.62 NM_020396 980
    PLAGL1 Pleiomorphic adenoma gene-like 1 0.62 NM_006718 981
    MAPK13 Mitogen-activated protein kinase 13 0.619 NM_002754 982
    PSCA Prostate stem cell antigen 0.619 NM_005672 983
    DOCK9 Dedicator of cytokinesis 9 0.618 NM_015296 984
    M6PRBP1 Mannose-6-phosphate receptor binding 0.618 NM_005817 985
    protein 1
    CCNG2 Cyclin G2 0.617 NM_004354 986
    BNC2 Basonuclin 2 0.617 BX641030 987
    OSBPL10 Oxysterol binding protein-like 10 0.616 NM_017784 988
    SEQ_ID_#989 CDNA FLJ41623 fis, clone CTONG3009227 0.616 AK123617 989
    PTK6 PTK6 protein tyrosine kinase 6 0.615 NM_005975 990
    MGC13159 Hypothetical protein MGC13159 0.615 NM_032927 991
    KNS2 Kinesin 2 60/70 kDa 0.615 NM_005552 992
    BNIPL BCL2/adenovirus E1B 19 kD interacting 0.615 NM_138278 993
    protein like
    OCA2 Oculocutaneous albinism II (pink-eye 0.614 NM_000275 994
    dilution homolog, mouse)
    TRPC1 Transient receptor potential cation 0.614 NM_003304 995
    channel, subfamily C, member 1
    TMEM61 Transmembrane protein 61 0.613 NM_182532 996
    MAFB V-maf musculoaponeurotic fibrosarcoma 0.612 NM_005461 997
    oncogene homolog B (avian)
    MTERFD2 MTERF domain containing 2 0.612 NM_182501 998
    FBXL16 F-box and leucine-rich repeat protein 16 0.612 NM_153350 999
    TAB3 TAK1-binding protein 3 0.612 NM_152787 1000
    FLJ32001 Chromosome 1 open reading frame 71 0.612 NM_152609 1001
    SEQ_ID_#1002 Homo sapiens, clone IMAGE: 2960615, 0.612 BC033124 1002
    mRNA
    SEQ_ID_#1003 CDNA FLJ41489 fis, clone BRTHA2004582 0.611 AK123483 1003
    SEQ_ID_#1004 Similar to RIKEN cDNA 9930021J17 0.611 XM_373035 1004
    SEQ_ID_#1005 Full-length cDNA clone CS0DF012YD09 of 0.61 BX460266 1005
    Fetal brain of Homo sapiens (human)
    ABHD6 Abhydrolase domain containing 6 0.609 NM_020676 1006
    SMURF1 SMAD specific E3 ubiquitin protein ligase 1 0.609 NM_020429 1007
    SNAPC3 Small nuclear RNA activating complex, 0.608 NM_003084 1008
    polypeptide 3, 50 kDa
    AADAT Aminoadipate aminotransferase 0.608 NM_016228 1009
    VDP Vesicle docking protein p115 0.607 NM_003715 1010
    TOB1 Transducer of ERBB2, 1 0.607 NM_005749 1011
    TJP1 Tight junction protein 1 (zona occludens 0.607 NM_003257 1012
    1)
    RHOB Ras homolog gene family, member B 0.607 NM_004040 1013
    C1orf128 Chromosome 1 open reading frame 128 0.606 NM_020362 1014
    PLD1 Phospholipase D1, phophatidylcholine- 0.606 NM_002662 1015
    specific
    TUBB3 Tubulin, beta 3 0.605 NM_006086 1016
    RALA V-ral simian leukemia viral oncogene 0.604 NM_005402 1017
    homolog A (ras related)
    GNAI3 Guanine nucleotide binding protein (G 0.604 NM_006496 1018
    protein), alpha inhibiting activity
    polypeptide 3
    CPNE8 Copine VIII 0.603 NM_153634 1019
    PPID Peptidylprolyl isomerase D (cyclophilin D) 0.603 NM_005038 1020
    HIF1A Hypoxia-inducible factor 1, alpha subunit 0.603 NM_001530 1021
    (basic helix-loop-helix transcription
    factor)
    RASAL1 RAS protein activator like 1 (GAP1 like) 0.602 NM_004658 1022
    RINT-1 Rad50-interacting protein 1 0.602 NM_021930 1023
    RHOF Ras homolog gene family, member F (in 0.602 NM_019034 1024
    filopodia)
    MAL Mal, T-cell differentiation protein 0.601 NM_002371 1025
    PTDSR Phosphatidylserine receptor 0.601 NM_015167 1026
    SC5DL Sterol-C5-desaturase (ERG3 delta-5- 0.6 NM_001024956 1027
    desaturase homolog, fungal)-like
    ANKRD6 Ankyrin repeat domain 6 0.6 NM_014942 1028
    UCHL5 Ubiquitin carboxyl-terminal hydrolase L5 0.6 NM_015984 1029
    LOC163590 Torsin A interacting protein 2 0.6 NM_145034 1030
    C8orf61 0.6 NM_001034061 1031
    FHOD3 Formin homology 2 domain containing 3 0.6 NM_025135 1032
    NCOA1 Nuclear receptor coactivator 1 0.599 NM_003743 1033
    PLA2G12A Phospholipase A2, group XIIA 0.599 NM_030821 1034
    ELOVL6 ELOVL family member 6, elongation of 0.599 NM_024090 1035
    long chain fatty acids (FEN1/Elo2,
    SUR4/Elo3-like, yeast)
    RAB2 RAB2, member RAS oncogene family 0.599 NM_002865 1036
    C17orf39 Chromosome 17 open reading frame 39 0.598 NM_024052 1037
    FLJ20582 Hypothetical protein FLJ20582 0.598 NM_014106 1038
    AOX1 Aldehyde oxidase 1 0.597 NM_001159 1039
    MALT1 Mucosa associated lymphoid tissue 0.596 NM_006785 1040
    lymphoma translocation gene 1
    CSNK1E Casein kinase 1, epsilon 0.595 NM_152221 1041
    MTPN Myotrophin 0.595 NM_145808 1042
    SLIC1 Selectin ligand interactor cytoplasmic-1 0.594 NM_153337 1043
    C20orf133 0.593 NM_001033086 1044
    EMP1 Epithelial membrane protein 1 0.593 NM_001423 1045
    C1orf58 Chromosome 1 open reading frame 58 0.593 NM_144695 1046
    BCOR BCL6 co-repressor 0.593 NM_017745 1047
    CA12 Carbonic anhydrase XII 0.592 AK022350 1048
    C10orf12 Chromosome 10 open reading frame 12 0.592 NM_015652 1049
    ACOX2 Acyl-Coenzyme A oxidase 2, branched 0.592 NM_003500 1050
    chain
    C20orf111 Chromosome 20 open reading frame 111 0.591 NM_016470 1051
    RNF11 Ring finger protein 11 0.591 NM_014372 1052
    SEQ_ID_#1055 CDNA FLJ39000 fis, clone NT2RI2022468 0.591 BX538337 1053
    PAQR5 Progestin and adipoQ receptor family 0.591 NM_017705 1054
    member V
    LATS2 LATS, large tumor suppressor, homolog 2 0.59 NM_014572 1055
    (Drosophila)
    FABP5 Fatty acid binding protein 5 (psoriasis- 0.59 NM_001444 1056
    associated)
    FALZ Fetal Alzheimer antigen 0.589 NM_182641 1057
    SEQ_ID_#1058 CDNA clone IMAGE: 4800262 0.589 BC040182 1058
    PIM1 Pim-1 oncogene 0.589 NM_002648 1059
    SEQ_ID_#1060 MRNA; cDNA DKFZp564O0862 (from 0.589 AL080095 1060
    clone DKFZp564O0862)
    SYNE2 Spectrin repeat containing, nuclear 0.589 NM_015180 1061
    envelope 2
    COL4A3BP Collagen, type IV, alpha 3 (Goodpasture 0.589 NM_005713 1062
    antigen) binding protein
    ACADL Acyl-Coenzyme A dehydrogenase, long 0.588 NM_001608 1063
    chain
    LOC286297; Hypothetical protein LOC286297 0.588 AK097152 1064
    bA251O17.4
    SEQ_ID_#1065 0.588 NM_032835 1065
    TM4SF13 Tetraspanin 13 0.588 NM_014399 1066
    NSE1 NSE1 0.588 NM_145175 1067
    KIF1B Kinesin family member 1B 0.587 NM_015074 1068
    SEQ_ID_#1069 0.587 BC036262 1069
    RAP1GDS1 RAP1, GTP-GDP dissociation stimulator 1 0.587 NM_021159 1070
    SMCX Smcy homolog, X-linked (mouse) 0.587 NM_004187 1071
    KIAA1991 Hypothetical protein KIAA1991 0.586 XM_495886 1072
    TYRO3 TYRO3 protein tyrosine kinase 0.586 NM_006293 1073
    NFE2L2 Nuclear factor (erythroid-derived 2)-like 2 0.586 NM_006164 1074
    SEQ_ID_#1075 603615533F1 NIH_MGC_110 Homo 0.586 BM006561 1075
    sapiens cDNA clone IMAGE: 5421225 5′,
    mRNA sequence.
    GALNT12 UDP-N-acetyl-alpha-D- 0.586 NM_024642 1076
    galactosamine:polypeptide N-
    acetylgalactosaminyltransferase 12
    (GalNAc-T12)
    CHP Calcium binding protein P22 0.586 NM_007236 1077
    SESN2 Sestrin 2 0.586 NM_031459 1078
    MGC9913 Hypothetical protein MGC9913 0.585 XM_378178 1079
    HTR3B 5-hydroxytryptamine (serotonin) receptor 0.585 NM_006028 1080
    3B
    ACOT11 Thioesterase, adipose associated 0.585 NM_147161 1081
    LOC221362 Hypothetical protein LOC221362 0.584 AK091117 1082
    SEC14L1 SEC14-like 1 (S. cerevisiae) 0.584 NM_003003 1083
    MYOZ1 Myozenin 1 0.584 NM_021245 1084
    FBXW11 F-box and WD-40 domain protein 11 0.584 NM_012300 1085
    CHMP2B Chromatin modifying protein 2B 0.584 NM_014043 1086
    CRYL1 Crystallin, lambda 1 0.583 NM_015974 1087
    FLJ10178 Hypothetical protein FLJ10178 0.583 NM_018015 1088
    LOC126295 Hypothetical protein LOC126295 0.583 NM_173480 1089
    LGMN Legumain 0.583 NM_001008530 1090
    MCFD2 Multiple coagulation factor deficiency 2 0.583 NM_139279 1091
    GRK4 G protein-coupled receptor kinase 4 0.582 L34408 1092
    PGM1 Phosphoglucomutase 1 0.581 NM_002633 1093
    FER Fer (fps/fes related) tyrosine kinase 0.581 NM_005246 1094
    (phosphoprotein NCP94)
    ZDHHC21 Zinc finger, DHHC-type containing 21 0.581 NM_178566 1095
    DOCK3 Dedicator of cytokinesis 3 0.58 NM_004947 1096
    PI4KII Phosphatidylinositol 4-kinase type II 0.58 NM_018425 1097
    RUSC2 RUN and SH3 domain containing 2 0.58 NM_014806 1098
    SEQ_ID_#1099 CDNA FLJ35001 fis, clone OCBBF2011887 0.579 AK123847 1099
    WDFY3 WD repeat and FYVE domain containing 3 0.578 NM_014991 1100
    TRERF1 Transcriptional regulating factor 1 0.578 NM_033502 1101
    NAGK N-acetylglucosamine kinase 0.578 NM_017567 1102
    RBM25; S164; Homo sapiens mRNA; cDNA 0.578 AL832314 1103
    RNPC7 DKFZp667O2119 (from clone
    DKFZp667O2119).
    FAM62B Family with sequence similarity 62 (C2 0.577 NM_020728 1104
    domain containing) member B
    ANKH Ankylosis, progressive homolog (mouse) 0.577 NM_054027 1105
    SEQ_ID_#1106 0.576 XM_379938 1106
    SLC13A4 Solute carrier family 13 (sodium/sulfate 0.576 NM_012450 1107
    symporters), member 4
    CDS1 CDP-diacylglycerol synthase 0.576 NM_001263 1108
    (phosphatidate cytidylyltransferase) 1
    KDELR3 KDEL (Lys-Asp-Glu-Leu) endoplasmic 0.576 NM_006855 1109
    reticulum protein retention receptor 3
    HIPK2 synonym: PRO0593; homeodomain- 0.575 NM_014075 1110
    interacting protein kinase 2;
    go_component: cytoplasm [goid
    0005737] [evidence ISS];
    go_component: nucleus [goid 0005634]
    [evidence IDA] [pmid 12220523];
    go_component: nuclear body [goid
    0016604] [evidence TAS] [pmid
    14626429]; go_function: ATP binding
    [goid 0005524] [evidence IEA];
    go_function: virion binding [goid
    0046790] [evidence IPI] [pmid
    14990717]; go_function: protein binding
    [goid 0005515] [evidence IPI] [pmid
    12220523]; go_function: transferase
    activity [goid 0016740] [evidence IEA];
    go_function: transcription corepressor
    activity [goid 0003714] [evidence TAS]
    [pmid 9748262]; go_function: protein
    serine/threonine kinase activity [goid
    0004674] [evidence IEA]; go_process:
    apoptosis [goid 0006915] [evidence IEA];
    go_process: transcription [goid 0006350]
    [evidence IEA]; go_process: virus-host
    interaction [goid 0019048] [evidence
    NAS] [pmid 14990717]; go_process:
    protein amino acid phosphorylation [goid
    0006468] [evidence IEA]; go_process:
    positive regulation of JNK cascade [goid
    0046330] [evidence IMP] [pmid
    14678985]; go_process: regulation of
    transcription, DNA-dependent [goid
    0006355] [evidence IEA]; go_process:
    regulation of progression through cell
    cycle [goid 0000074] [evidence NAS]
    [pmid 14990717]; go_process: induction
    of apoptosis by intracellular signals [goid
    0008629] [evidence NAS] [pmid
    15122315]; go_process: positive
    regulation of transforming growth factor
    beta receptor signaling pathway [goid
    0030511] [evidence IMP] [pmid
    14678985]; Homo sapiens homeodomain
    interacting protein kinase 2 (HIPK2),
    mRNA.
    PBEF1 Pre-B-cell colony enhancing factor 1 0.575 NM_005746 1111
    ZNF117 Zinc finger protein 117 (HPF9) 0.574 NM_015852 1112
    CFTR Cystic fibrosis transmembrane 0.574 NM_000492 1113
    conductance regulator, ATP-binding
    cassette (sub-family C, member 7)
    PER3 Period homolog 3 (Drosophila) 0.573 NM_016831 1114
    KRTHA3A Keratin, hair, acidic, 3A 0.573 NM_004138 1115
    SGEF Src homology 3 domain-containing 0.573 NM_015595 1116
    guanine nucleotide exchange factor
    ENSA Endosulfine alpha 0.572 NM_207043 1117
    WNK4 WNK lysine deficient protein kinase 4 0.572 NM_032387 1118
    SLC2A13 Solute carrier family 2 (facilitated glucose 0.572 NM_052885 1119
    transporter), member 13
    ZZANK1 Mindbomb homolog 2 (Drosophila) 0.572 NM_080875 1120
    CYYR1 Cysteine/tyrosine-rich 1 0.572 NM_052954 1121
    TRIB3 Tribbles homolog 3 (Drosophila) 0.571 NM_021158 1122
    C1orf108 Chromosome 1 open reading frame 108 0.571 NM_024595 1123
    SEQ_ID_#1024 0.571 AL031723 1124
    RNF24 Ring finger protein 24 0.571 NM_007219 1125
    H2BFS H2B histone family, member S 0.571 NM_017445 1126
    DKK4 Dickkopf homolog 4 (Xenopus laevis) 0.569 NM_014420 1127
    MXI1 MAX interactor 1 0.569 NM_001008541 1128
    CABLES1 Cdk5 and Abl enzyme substrate 1 0.569 NM_138375 1129
    HECTD1 HECT domain containing 1 0.568 NM_015382 1130
    MAF 0.567 NM_001031804 1131
    PCGF2 Polycomb group ring finger 2 0.567 BM695150 1132
    PLXDC2 Plexin domain containing 2 0.567 AK127644 1133
    WDR41 WD repeat domain 41 0.567 NM_018268 1134
    TSPYL4 TSPY-like 4 0.566 NM_021648 1135
    UPP1 Uridine phosphorylase 1 0.565 NM_003364 1136
    TMEM37 Transmembrane protein 37 0.565 NM_183240 1137
    FBXW7 F-box and WD-40 domain protein 7 0.565 NM_001013415 1138
    (archipelago homolog, Drosophila)
    RPIB9 Rap2-binding protein 9 0.565 NM_138290 1139
    SLC1A3 Solute carrier family 1 (glial high affinity 0.564 NM_004172 1140
    glutamate transporter), member 3
    FAM3D Family with sequence similarity 3, 0.564 NM_138805 1141
    member D
    TSC22D2 TSC22 domain family, member 2 0.563 NM_014779 1142
    DSC1 Desmocollin 1 0.563 NM_004948 1143
    SRPX2 Sushi-repeat-containing protein, X-linked 2 0.563 NM_014467 1144
    GRB14 Growth factor receptor-bound protein 14 0.563 NM_004490 1145
    COBL Cordon-bleu homolog (mouse) 0.563 NM_015198 1146
    HIST1H2BF Histone 1, H2bf 0.563 NM_003522 1147
    C10orf57 Chromosome 10 open reading frame 57 0.563 NM_025125 1148
    SEQ_ID_#1149 Transcribed locus 0.562 BM993105 1149
    MELL1 Mel transforming oncogene-like 1 0.562 NM_033467 1150
    SHMT1 Serine hydroxymethyltransferase 1 0.562 NM_004169 1151
    (soluble)
    SEQ_ID_#1152 0.562 NM_032751 1152
    C14orf78 Chromosome 14 open reading frame 78 0.561 XM_290629 1153
    DRCTNNB1A Down-regulated by Ctnnb1, a 0.433 NM_032581 1154
    SLC24A3 Solute carrier family 24 0.56 NM_020689 1155
    (sodium/potassium/calcium exchanger),
    member 3
    RC3H1 0.56 NM_172071 1156
    SEQ_ID_#1157 CDNA: FLJ23573 fis, clone LNG12520 0.559 AK027226 1157
    SYAP1 Synapse associated protein 1, SAP47 0.559 NM_032796 1158
    homolog (Drosophila)
    D4S234E DNA segment on chromosome 4 (unique) 0.559 NM_014392 1159
    234 expressed sequence
    SEQ_ID_#1160 602540462F1 NIH_MGC_59 Homo 0.559 BG495068 1160
    sapiens cDNA clone IMAGE: 4671519 5′,
    mRNA sequence.
    B3GNT5 UDP-GlcNAc: betaGal beta-1,3-N- 0.559 NM_032047 1161
    acetylglucosaminyltransferase 5
    SCGB2A1 Secretoglobin, family 2A, member 1 0.558 NM_002407 1162
    ZNF416 Zinc finger protein 416 0.558 NM_017879 1163
    LOC146174 Chromosome 16 open reading frame 52 0.557 NM_173501 1164
    TPM4 Tropomyosin 4 0.556 NM_003290 1165
    KRTHA2 Keratin, hair, acidic, 2 0.556 NM_002278 1166
    CPVL Carboxypeptidase, vitellogenic-like 0.555 NM_019029 1167
    GADD45B Growth arrest and DNA-damage- 0.555 NM_015675 1168
    inducible, beta
    SEQ_ID_#1169 BX109361 NCI_CGAP_Lu5 Homo sapiens 0.554 BX109361 1169
    cDNA clone IMAGp998B174679;
    IMAGE: 1908400, mRNA sequence.
    SLC5A1 Solute carrier family 5 (sodium/glucose 0.554 NM_000343 1170
    cotransporter), member 1
    HNMT Histamine N-methyltransferase 0.554 NM_001024074 1171
    SEQ_ID_#1172 CDNA FLJ31407 fis, clone NT2NE2000137 0.554 AK055969 1172
    SNX24 Sorting nexing 24 0.554 NM_014035 1173
    CPD Carboxypeptidase D 0.553 NM_001304 1174
    SEQ_ID_#1175 Transcribed locus 0.553 BX116062 1175
    LOC162993 Hypothetical protein LOC162993 0.553 XM_091914 1176
    CUL4B Cullin 4B 0.552 NM_003588 1177
    H41 Hypothetical protein H41 0.551 NM_017548 1178
    SEQ_ID_#1179 CDNA clone IMAGE: 4830452 0.551 BC034636 1179
    SNX14 Sorting nexin 14 0.551 NM_153816 1180
    ZNRF1 Zinc and ring finger 1 0.551 NM_032268 1181
    AHCY S-adenosylhomocysteine hydrolase 0.551 NM_000687 1182
    SEQ_ID_#1183 Transcribed locus, strongly similar to 0.551 BF510602 1183
    XP_517083.1 PREDICTED: similar to
    hypothetical protein MGC13159 [Pan
    troglodytes]
    CSTB Cystatin B (stefin B) 0.551 NM_000100 1184
    RASAL2 RAS protein activator like 2 0.549 NM_004841 1185
    ITPR2 Inositol 1,4,5-triphosphate receptor, type 2 0.548 NM_002223 1186
    CORO1C Coronin, actin binding protein, 1C 0.547 NM_014325 1187
    IL22RA1 Interleukin 22 receptor, alpha 1 0.546 NM_021258 1188
    IMPA2 Inositol(myo)-1(or 4)-monophosphatase 2 0.545 NM_014214 1189
    PTN Pleiotrophin (heparin binding growth 0.545 NM_002825 1190
    factor 8, neurite growth-promoting factor
    1)
    SEQ_ID_#1191 Transcribed locus 0.545 BX327653 1191
    PBX3 Pre-B-cell leukemia transcription factor 3 0.545 NM_006195 1192
    ST7L Suppression of tumorigenicity 7 like 0.544 AK128799 1193
    FLJ20674 Hypothetical protein FLJ20674 0.544 NM_019086 1194
    JARID1B Jumonji, AT rich interactive domain 1B 0.543 NM_006618 1195
    (RBP2-like)
    UNC13B Unc-13 homolog B (C. elegans) 0.543 NM_006377 1196
    SEC24A SEC24 related gene family, member A (S. cerevisiae) 0.542 XM_094581 1197
    MXD1 MAX dimerization protein 1 0.541 NM_002357 1198
    ROR1 Receptor tyrosine kinase-like orphan 0.541 NM_005012 1199
    receptor 1
    SLC22A15 Solute carrier family 22 (organic cation 0.54 NM_018420 1200
    transporter), member 15
    GDPD3 0.54 NM_001031718 1201
    LOC285671 Ring finger protein 180 0.539 NM_178532 1202
    COL21A1 Collagen, type XXI, alpha 1 0.538 NM_030820 1203
    SEQ_ID_#1204 602540462F1 NIH_MGC_59 Homo 0.538 BG495068 1204
    sapiens cDNA clone IMAGE: 4671519 5′,
    mRNA sequence.
    EHBP1 EH domain binding protein 1 0.537 NM_015252 1205
    FTH1 Ferritin, heavy polypeptide 1 0.537 NM_002032 1206
    LOC159090 Similar to hypothetical protein MGC17347 0.537 NM_145284 1207
    COQ6 synonym: CGI-10; isoform a is encoded 0.537 NM_015940 1208
    by transcript variant 1; go_function: FAD
    binding [goid 0050660] [evidence IEA];
    go_function: monooxygenase activity
    [goid 0004497] [evidence IEA];
    go_function: ubiquinone biosynthesis
    monooxygenase activity [goid 0015997]
    [evidence IEA]; go_process: metabolism
    [goid 0008152] [evidence IEA];
    go_process: electron transport [goid
    0006118] [evidence IEA]; go_process:
    ubiquinone biosynthesis [goid 0006744]
    [evidence IEA]; go_process: aromatic
    compound metabolism [goid 0006725]
    [evidence IEA]; Homo sapiens coenzyme
    Q6 homolog (yeast) (COQ6), transcript
    variant
    1, mRNA.
    SEQ_ID_#1209 UI-CF-DU1-adq-o-11-0-UI.s1 UI-CF-DU1 0.537 BM978616 1209
    Homo sapiens cDNA clone UI-CF-DU1-
    adq-o-11-0-UI 3′, mRNA sequence.
    SFT2D2 SFT2 domain containing 2 0.536 NM_199344 1210
    DEGS2 Degenerative spermatocyte homolog 2, 0.536 BE512716 1211
    lipid desaturase (Drosophila)
    ERO1L ERO1-like (S. cerevisiae) 0.536 NM_014584 1212
    FLJ32421 Chromosome 1 open reading frame 58 0.535 NM_144695 1213
    MTHFD2L Methylenetetrahydrofolate dehydrogenase 0.534 NM_001004346 1214
    (NADP+ dependent) 2-like
    PHC1 Polyhomeotic-like 1 (Drosophila) 0.533 NM_004426 1215
    IL13RA1 Interleukin 13 receptor, alpha 1 0.533 NM_001560 1216
    MINA MYC induced nuclear antigen 0.533 NM_032778 1217
    UBE2H Ubiquitin-conjugating enzyme E2H (UBC8 0.533 NM_003344 1218
    homolog, yeast)
    SEQ_ID_#1219 Homo sapiens, clone IMAGE: 4413555, 0.532 BG034859 1219
    mRNA
    C14orf45 Chromosome 14 open reading frame 45 0.532 NM_025057 1220
    ABTB2 Ankyrin repeat and BTB (POZ) domain 0.532 NM_145804 1221
    containing 2
    SLC35F2 Solute carrier family 35, member F2 0.532 NM_017515 1222
    GMPPB GDP-mannose pyrophosphorylase B 0.531 NM_013334 1223
    INADL InaD-like (Drosophila) 0.531 NM_170605 1224
    ANKRD46 Ankyrin repeat domain 46 0.531 NM_198401 1225
    WDR26 WD repeat domain 26 0.531 NM_025160 1226
    ZYG11A Zyg-11 homolog A (C. elegans) 0.53 NM_001004339 1227
    ELL2 Elongation factor, RNA polymerase II, 2 0.53 NM_012081 1228
    ARRDC3 Arrestin domain containing 3 0.53 NM_020801 1229
    MBD2 Apoptosis-inducing factor (AIF)-like 0.529 NM_032797 1230
    mitochondrion-associated inducer of
    death
    VARSL Valyl-tRNA synthetase 2-like 0.529 NM_020442 1231
    UBE2E2 Ubiquitin-conjugating enzyme E2E 2 0.529 NM_152653 1232
    (UBC 4/5 homolog, yeast)
    C1orf168 Chromosome 1 open reading frame 168 0.529 NM_001004303 1233
    TFCP2L1 Transcription factor CP2-like 1 0.528 NM_014553 1234
    LOC284825 Hypothetical protein LOC284825 0.528 AI311303 1235
    CAPN5 Calpain 5 0.528 NM_004055 1236
    VIT Vitrin 0.528 NM_053276 1237
    SEQ_ID_#1238 0.528 NM_032746 1238
    DKFZp434C0328 Hypothetical protein DKFZp434C0328 0.528 NM_017577 1239
    PLEKHG1 synonyms: FLJ31738, KIAA1209; Homo 0.527 NM_001029884 1240
    sapiens pleckstrin homology domain
    containing, family G (with RhoGef
    domain) member 1 (PLEKHG1), mRNA.
    CD207 CD207 antigen, langerin 0.526 NM_015717 1241
    NOV Nephroblastoma overexpressed gene 0.526 NM_002514 1242
    LRFN5 Leucine rich repeat and fibronectin type 0.526 NM_152447 1243
    III domain containing 5
    7-Mar Membrane-associated ring finger (C3HC4) 7 0.525 NM_022826 1244
    RAB6B RAB6B, member RAS oncogene family 0.524 NM_016577 1245
    MYEOV Myeloma overexpressed gene (in a subset 0.524 NM_138768 1246
    of t(11; 14) positive multiple myelomas)
    MDFIC MyoD family inhibitor domain containing 0.524 NM_199072 1247
    SLC38A2 Solute carrier family 38, member 2 0.524 NM_018976 1248
    SEQ_ID_#1249 Transcribed locus 0.523 BM712901 1249
    MRPS10 Mitochondrial ribosomal protein S10 0.523 NM_018141 1250
    FLJ13910 Hypothetical protein FLJ13910 0.523 NM_022780 1251
    ZNF92 Zinc finger protein 92 (HTF12) 0.521 NM_007139 1252
    SEQ_ID_#1253 CDNA FLJ30885 fis, clone FEBRA2004987 0.52 AK055447 1253
    ST6GALNAC1 ST6 (alpha-N-acetyl-neuraminyl-2,3- 0.52 NM_018414 1254
    beta-galactosyl-1,3)-N-
    acetylgalactosaminide alpha-2,6-
    sialyltransferase 1
    DSC2 Desmocollin 2 0.518 NM_004949 1255
    PNMA1 Paraneoplastic antigen MA1 0.518 NM_006029 1256
    MGC40368 Hypothetical protein MGC40368 0.517 NM_152772 1257
    PDLIM5 PDZ and LIM domain 5 0.516 NM_001011515 1258
    SH3D19 SH3 domain protein D19 0.516 NM_001009555 1259
    C1orf181 Hypothetical protein FLJ20729 0.515 NM_017953 1260
    LTB4DH Leukotriene B4 12- 0.515 NM_012212 1261
    hydroxydehydrogenase
    WDR5B WD repeat domain 5B 0.514 NM_019069 1262
    TSCOT Thymic stromal co-transporter 0.514 NM_033051 1263
    C1orf21 Chromosome 1 open reading frame 21 0.514 NM_030806 1264
    SLC27A6 Solute carrier family 27 (fatty acid 0.513 NM_001017372 1265
    transporter), member 6
    FLJ25179 C3 and PZP-like, alpha-2-macroglobulin 0.513 NM_144670 1266
    domain containing 9
    EGLN1 Egl nine homolog 1 (C. elegans) 0.512 NM_022051 1267
    PHTF2 Putative homeodomain transcription 0.511 NM_020432 1268
    factor 2
    GP1BB Glycoprotein Ib (platelet), beta 0.511 NM_000407 1269
    polypeptide
    BCAR3 Breast cancer anti-estrogen resistance 3 0.51 NM_003567 1270
    LNX2 Ligand of numb-protein X 2 0.508 NM_153371 1271
    RPL23AP7; Homo sapiens cDNA FLJ30702 fis, clone 0.507 AK055264 1272
    RPL23AL1; FCBBF2001001.
    bA395L14.9
    CLEC3B C-type lectin domain family 3, member B 0.507 NM_003278 1273
    C18orf9 Chromosome 18 open reading frame 9 0.507 NM_024899 1274
    CRTAC1 Cartilage acidic protein 1 0.507 NM_018058 1275
    C18orf19 Chromosome 18 open reading frame 19 0.506 NM_152352 1276
    CNFN Cornifelin 0.506 NM_032488 1277
    HIST2H2BE Histone 2, H2be 0.506 NM_003528 1278
    WASL Wiskott-Aldrich syndrome-like 0.506 NM_003941 1279
    FLRT2 Fibronectin leucine rich transmembrane 0.505 NM_013231 1280
    protein 2
    SASH1 SAM and SH3 domain containing 1 0.505 NM_015278 1281
    GPSM2 G-protein signalling modulator 2 (AGS3- 0.504 NM_013296 1282
    like, C. elegans)
    PLK2 Polo-like kinase 2 (Drosophila) 0.504 NM_006622 1283
    SPRR3 Small proline-rich protein 3 0.504 NM_005416 1284
    CAST Calpastatin 0.503 NM_001750 1285
    RNMT RNA (guanine-7-) methyltransferase 0.503 NM_003799 1286
    K5B Keratin 5b 0.503 NM_173352 1287
    TM4SF12 Tetraspanin 12 0.503 NM_012338 1288
    RRAGD Ras-related GTP binding D 0.503 NM_021244 1289
    MT1F Metallothionein 1F (functional) 0.503 NM_005949 1290
    RBM35A 0.502 NM_001034915 1291
    LYNX1 Ly6/neurotoxin 1 0.501 NM_023946 1292
    HK2 Hexokinase 2 0.5 NM_000189 1293
    C8orf48 Hypothetical protein FLJ25402 0.5 NM_001007090 1294
    MOSPD1 Motile sperm domain containing 1 0.5 NM_019556 1295
    PMAIP1 Phorbol-12-myristate-13-acetate-induced 0.499 NM_021127 1296
    protein 1
    TRPS1 Trichorhinophalangeal syndrome I 0.499 NM_014112 1297
    FLJ14054 Hypothetical protein FLJ14054 0.499 NM_024563 1298
    SLITL2 Slit-like 2 (Drosophila) 0.498 NM_138440 1299
    CTTNBP2 Cortactin binding protein 2 0.498 NM_033427 1300
    UBE2G1 Ubiquitin-conjugating enzyme E2G 1 0.497 NM_003342 1301
    (UBC7 homolog, C. elegans)
    SEQ_ID_#1302 UI-E-EJ1-ajs-c-01-0-UI.r1 UI-E-EJ1 Homo 0.497 BQ185835 1302
    sapiens cDNA clone UI-E-EJ1-ajs-c-01-0-
    UI 5′, mRNA sequence.
    CDKN2B Cyclin-dependent kinase inhibitor 2B 0.496 NM_004936 1303
    (p15, inhibits CDK4)
    KIAA0232 KIAA0232 gene product 0.496 NM_014743 1304
    LRRC20 Leucine rich repeat containing 20 0.495 NM_018205 1305
    SOCS6 Suppressor of cytokine signaling 6 0.495 NM_004232 1306
    KLK13 Kallikrein 13 0.495 NM_015596 1307
    ZDHHC15 Zinc finger, DHHC-type containing 15 0.494 NM_144969 1308
    UNC84A Unc-84 homolog A (C. elegans) 0.494 NM_025154 1309
    LOC147645 Hypothetical protein LOC147645 0.494 XM_085831 1310
    FLJ14011 Zinc finger protein 667 0.494 NM_022103 1311
    HIST1H3D Histone 1, H3d 0.493 NM_003530 1312
    TIMP2 Tissue inhibitor of metalloproteinase 2 0.492 NM_003255 1313
    ETNK2 Ethanolamine kinase 2 0.492 NM_018208 1314
    SLC6A1 Solute carrier family 6 (neurotransmitter 0.492 NM_003042 1315
    transporter, GABA), member 1
    MARCKS Myristoylated alanine-rich protein kinase 0.491 NM_002356 1316
    C substrate
    MRCL3 Myosin regulatory light chain MRCL3 0.489 NM_006471 1317
    Gcom1 GRINL1A combined protein 0.488 NM_001018100 1318
    C21orf5 Chromosome 21 open reading frame 5 0.488 NM_005128 1319
    FUT11 Fucosyltransferase 11 (alpha (1,3) 0.486 NM_173540 1320
    fucosyltransferase)
    CYP2C18 Cytochrome P450, family 2, subfamily C, 0.486 NM_000772 1321
    polypeptide 18
    CTH Cystathionase (cystathionine gamma- 0.485 NM_001902 1322
    lyase)
    CYP2C9 Cytochrome P450, family 2, subfamily C, 0.485 NM_000771 1323
    polypeptide 9
    FLJ11151 Hypothetical protein FLJ11151 0.484 NM_018340 1324
    LOC387758 Similar to RIKEN cDNA 1110018M03 0.482 NM_203371 1325
    KIAA1345 KIAA1345 protein 0.481 XM_106386 1326
    GNG12 Guanine nucleotide binding protein (G 0.48 NM_018841 1327
    protein), gamma 12
    SHRM Shroom 0.48 NM_020859 1328
    SEQ_ID_#1329 Transcribed locus 0.48 BG191459 1329
    PHACTR2 Phosphatase and actin regulator 2 0.48 NM_014721 1330
    USP13 Ubiquitin specific protease 13 0.479 NM_003940 1331
    (isopeptidase T-3)
    CIDEA Cell death-inducing DFFA-like effector a 0.479 NM_001279 1332
    ETV1 Ets variant gene 1 0.478 NM_004956 1333
    MAP3K4 Mitogen-activated protein kinase kinase 0.476 NM_005922 1334
    kinase 4
    HIC MyoD family inhibitor domain containing 0.476 NM_199072 1335
    LOC96610 Hypothetical protein similar to KIAA0187 0.476 NM_080926 1336
    gene product
    DEGS1 Degenerative spermatocyte homolog 1, 0.475 NM_003676 1337
    lipid desaturase (Drosophila)
    SEQ_ID_#1338 CDNA: FLJ22256 fis, clone HRC02860 0.474 AK025909 1338
    HPSE Heparanase 0.473 NM_006665 1339
    KCNAB1 Potassium voltage-gated channel, shaker- 0.473 NM_003471 1340
    related subfamily, beta member 1
    BNIP3L BCL2/adenovirus E1B 19 kDa interacting 0.473 NM_004331 1341
    protein 3-like
    NPR3 Natriuretic peptide receptor C/guanylate 0.473 NM_000908 1342
    cyclase C (atrionatriuretic peptide
    receptor C)
    LOC388727 Hypothetical LOC388727 0.471 XM_373881 1343
    CYP26B1 Cytochrome P450, family 26, subfamily B, 0.471 NM_019885 1344
    polypeptide 1
    SLC38A4 Solute carrier family 38, member 4 0.47 NM_018018 1345
    LNX1 Ligand of numb-protein X 0.47 NM_032622 1346
    CFLAR CASP8 and FADD-like apoptosis regulator 0.469 NM_003879 1347
    MT1X Metallothionein 1X 0.468 NM_005952 1348
    PELI1 Pellino homolog 1 (Drosophila) 0.468 NM_020651 1349
    CNKSR3 CNKSR family member 3 0.468 NM_173515 1350
    SEQ_ID_#1351 AGENCOURT_7760686 NIH_MGC_92 0.468 BQ421887 1351
    Homo sapiens cDNA clone
    IMAGE: 6016357 5′, mRNA sequence.
    ITM2A Integral membrane protein 2A 0.467 NM_004867 1352
    DGAT2 Diacylglycerol O-acyltransferase homolog 0.467 NM_032564 1353
    2 (mouse)
    DKFZp434N2030 Hypothetical protein DKFZp434N2030 0.466 NM_001009894 1354
    WASF3 WAS protein family, member 3 0.466 NM_006646 1355
    LOC400960 Hypothetical gene supported by 0.466 AK056822 1356
    BC040598
    TTC22 Hypothetical protein FLJ20619 0.465 NM_017904 1357
    CHI3L1 Chitinase 3-like 1 (cartilage glycoprotein- 0.465 NM_001276 1358
    39)
    RBP7 Retinol binding protein 7, cellular 0.464 NM_052960 1359
    EGFL5 EGF-like-domain, multiple 5 0.464 XM_376905 1360
    PHLDA1 Pleckstrin homology-like domain, family 0.464 NM_007350 1361
    A, member 1
    CRIP2 Cysteine-rich protein 2 0.464 NM_001312 1362
    MYBBP1A MYB binding protein (P160) 1a 0.464 NM_014520 1363
    CPA4 Carboxypeptidase A4 0.462 NM_016352 1364
    PTP4A1 Protein tyrosine phosphatase type IVA, 0.462 NM_003463 1365
    member 1
    RBMS1 RNA binding motif, single stranded 0.461 NM_002897 1366
    interacting protein 1
    FZD7 Frizzled homolog 7 (Drosophila) 0.461 NM_003507 1367
    CLDN17 Claudin 17 0.46 NM_012131 1368
    FCER1A Fc fragment of IgE, high affinity I, 0.46 NM_002001 1369
    receptor for; alpha polypeptide
    PDZK8 PDZ domain containing 8 0.459 NM_173791 1370
    SPTLC1 Serine palmitoyltransferase, long chain 0.459 NM_178324 1371
    base subunit 1
    EPB41L4A Erythrocyte membrane protein band 4.1 0.458 NM_022140 1372
    like 4A
    FLJ39501 Cytochrome P450, family 2, subfamily E, 0.458 NM_173483 1373
    polypeptide 2 homolog
    ZNF430 Zinc finger protein 430 0.457 NM_025189 1374
    SEQ_ID_#1375 CDNA clone IMAGE: 4838152 0.457 BC034596 1375
    AGR2 Anterior gradient 2 homolog (Xenopus 0.456 NM_006408 1376
    laevis)
    RIOK3 RIO kinase 3 (yeast) 0.456 NM_003831 1377
    SNX9 Sorting nexin 9 0.456 NM_016224 1378
    SEQ_ID_#1379 Transcribed locus, strongly similar to 0.454 AW510697 1379
    NP_080835.1 thioredoxin-like 5 [Mus
    musculus]
    BCL10 B-cell CLL/lymphoma 10 0.453 NM_003921 1380
    AK3 Adenylate kinase 3-like 1 0.453 NM_013410 1381
    SEQ_ID_#1382 0.452 NM_014688 1382
    CMAS Cytidine monophosphate N- 0.452 NM_018686 1383
    acetylneuraminic acid synthetase
    SEQ_ID_#1384 Transcribed locus 0.451 AI632692 1384
    MYO6 Myosin VI 0.45 NM_004999 1385
    FLJ31153 Hypothetical protein FLJ31153 0.45 NM_144600 1386
    PPP1R2 Protein phosphatase 1, regulatory 0.449 NM_006241 1387
    (inhibitor) subunit 2
    LPIN1 Lipin 1 0.448 NM_145693 1388
    XK Kell blood group precursor (McLeod 0.448 NM_021083 1389
    phenotype)
    ACOT4 Peroxisomal acyl-CoA thioesterase 2B 0.448 NM_152331 1390
    CHAC2 Similar to RIKEN cDNA 2510006C20 gene 0.447 NM_001008708 1391
    ENC1 Ectodermal-neural cortex (with BTB-like 0.447 NM_003633 1392
    domain)
    UBL3 Ubiquitin-like 3 0.446 NM_007106 1393
    ACPP Acid phosphatase, prostate 0.446 NM_001099 1394
    SLC7A5 Solute carrier family 7 (cationic amino 0.445 NM_003486 1395
    acid transporter, y+ system), member 5
    C15orf29 Chromosome 15 open reading frame 29 0.444 NM_024713 1396
    WDR37 WD repeat domain 37 0.443 NM_014023 1397
    ZNF662 Zinc finger protein 662 0.442 NM_207404 1398
    LOC152831 Klotho beta like 0.442 NM_175737 1399
    FN5 B-cell CLL/lymphoma 7B 0.441 NM_020179 1400
    KIF21A Kinesin family member 21A 0.44 NM_017641 1401
    SPIRE1 Spire homolog 1 (Drosophila) 0.44 NM_020148 1402
    SLC7A11 Solute carrier family 7, (cationic amino 0.439 NM_014331 1403
    acid transporter, y+ system) member 11
    TEAD1 TEA domain family member 1 (SV40 0.438 NM_021961 1404
    transcriptional enhancer factor)
    SH3BGRL2 SH3 domain binding glutamic acid-rich 0.437 NM_031469 1405
    protein like 2
    PDZRN3 PDZ domain containing RING finger 3 0.436 NM_015009 1406
    PHGDH Phosphoglycerate dehydrogenase 0.435 NM_006623 1407
    CAP2 CAP, adenylate cyclase-associated 0.435 NM_006366 1408
    protein, 2 (yeast)
    PARP11 Poly (ADP-ribose) polymerase family, 0.435 NM_020367 1409
    member 11
    ALS2CR2 Amyotrophic lateral sclerosis 2 (juvenile) 0.433 NM_018571 1410
    chromosome region, candidate 2
    LOC168850 Hypothetical protein LOC168850 0.433 NM_176814 1411
    SMPDL3A Sphingomyelin phosphodiesterase, acid- 0.433 NM_006714 1412
    like 3A
    C1orf9 Chromosome 1 open reading frame 9 0.432 NM_014283 1413
    HLA-DQB2 Major histocompatibility complex, class II, 0.432 NM_182549 1414
    DQ beta 2
    ZA20D2 Zinc finger, A20 domain containing 2 0.431 NM_006007 1415
    SNX16 Sorting nexin 16 0.431 NM_022133 1416
    ITCH Itchy homolog E3 ubiquitin protein ligase 0.431 NM_031483 1417
    (mouse)
    MAMDC2 MAM domain containing 2 0.431 NM_153267 1418
    BEAN Brain expressed, associated with Nedd4 0.43 XM_375359 1419
    ABHD5 Abhydrolase domain containing 5 0.43 NM_016006 1420
    AGA Aspartylglucosaminidase 0.429 NM_000027 1421
    SPAG1 Sperm associated antigen 1 0.429 NM_003114 1422
    BOC Brother of CDO 0.428 NM_033254 1423
    MGST1 Microsomal glutathione S-transferase 1 0.428 NM_020300 1424
    C5orf13 Chromosome 5 open reading frame 13 0.427 NM_004772 1425
    PLEKHA5 Pleckstrin homology domain containing, 0.426 NM_019012 1426
    family A member 5
    ZNF555 Zinc finger protein 555 0.426 NM_152791 1427
    TADA3L Transcriptional adaptor 3 (NGG1 0.425 NM_133480 1428
    homolog, yeast)-like
    PRKACB Protein kinase, cAMP-dependent, 0.424 NM_002731 1429
    catalytic, beta
    HIST1H2BG Histone 1, H2bg 0.424 NM_003518 1430
    PALMD Palmdelphin 0.423 NM_017734 1431
    LOC136288 Hypothetical protein LOC136288 0.421 XM_059832 1432
    CALB2 Calbindin 2, 29 kDa (calretinin) 0.419 NM_001740 1433
    PLA2G4A Phospholipase A2, group IVA (cytosolic, 0.417 NM_024420 1434
    calcium-dependent)
    MT1H Metallothionein 1H 0.417 NM_005951 1435
    SEQ_ID_#1436 0.417 AL031602 1436
    SEQ_ID_#1437 Full-length cDNA clone CS0DD009YB17 of 0.417 AK000776 1437
    Neuroblastoma Cot 50-normalized of
    Homo sapiens (human)
    PFKFB3 6-phosphofructo-2-kinase/fructose-2,6- 0.415 NM_004566 1438
    biphosphatase 3
    C10orf45 Chromosome 10 open reading frame 45 0.415 AK096685 1439
    BPGM 2,3-bisphosphoglycerate mutase 0.415 NM_001724 1440
    EML1 Echinoderm microtubule associated 0.193 NM_001008707 1441
    protein like 1
    AKR1C1 Aldo-keto reductase family 1, member C1 0.414 NM_001353 1442
    (dihydrodiol dehydrogenase 1; 20-alpha
    (3-alpha)-hydroxysteroid dehydrogenase)
    TBC1D10 TBC1 domain family, member 10A 0.414 NM_031937 1443
    MN1 Meningioma (disrupted in balanced 0.414 NM_002430 1444
    translocation) 1
    LOC120379 Hypothetical protein BC019238 0.414 NM_138789 1445
    IL18 Interleukin 18 (interferon-gamma- 0.414 NM_001562 1446
    inducing factor)
    GSTA4 Glutathione S-transferase A4 0.413 NM_001512 1447
    LOC93622 Hypothetical protein BC006130 0.412 NM_138699 1448
    TNFRSF19 Tumor necrosis factor receptor 0.412 NM_148957 1449
    superfamily, member 19
    TMOD3 Tropomodulin 3 (ubiquitous) 0.41 NM_014547 1450
    C10orf99 Chromosome 10 open reading frame 99 0.406 NM_207373 1451
    ACAA2 Acetyl-Coenzyme A acyltransferase 2 0.404 NM_006111 1452
    (mitochondrial 3-oxoacyl-Coenzyme A
    thiolase)
    SEQ_ID_#1453 CDNA FLJ39842 fis, clone SPLEN2014293 0.404 AK097161 1453
    CNN3 Calponin 3, acidic 0.404 NM_001839 1454
    RPESP RPE-spondin 0.403 NM_153225 1455
    SLC16A9 Solute carrier family 16 (monocarboxylic 0.402 NM_194298 1456
    acid transporters), member 9
    FLJ42117 FLJ42117 protein 0.398 NM_198463 1457
    SYTL5 Synaptotagmin-like 5 0.398 NM_138780 1458
    WNK1 WNK lysine deficient protein kinase 1 0.397 NM_018979 1459
    TncRNA Trophoblast-derived noncoding RNA 0.395 AF001893 1460
    UACA Uveal autoantigen with coiled-coil 0.395 NM_001008224 1461
    domains and ankyrin repeats
    FRAS1 Fraser syndrome 1 0.394 NM_025074 1462
    KLHL24 DRE1 protein 0.393 NM_017644 1463
    RFK Riboflavin kinase 0.392 NM_018339 1464
    LOC92196 Similar to death-associated protein 0.392 NM_001017920 1465
    MT1E Metallothionein 1E (functional) 0.392 NM_175617 1466
    AKR1C3 Aldo-keto reductase family 1, member C3 0.392 NM_003739 1467
    (3-alpha hydroxysteroid dehydrogenase,
    type II)
    RAP2A RAP2A, member of RAS oncogene family 0.39 NM_021033 1468
    ZNF76 Zinc finger protein 76 (expressed in 0.389 NM_003427 1469
    testis)
    CHAC1 Hypothetical protein MGC4504 0.389 NM_024111 1470
    GATM Glycine amidinotransferase (L- 0.386 NM_001482 1471
    arginine:glycine amidinotransferase)
    NHLH2 Nescient helix loop helix 2 0.386 NM_005599 1472
    H-plk Zinc finger protein 117 (HPF9) 0.386 NM_015852 1473
    PANK1 Pantothenate kinase 1 0.385 NM_138316 1474
    RORA RAR-related orphan receptor A 0.384 NM_002943 1475
    AFF4 AF4/FMR2 family, member 4 0.383 NM_014423 1476
    MGC39372 Hypothetical protein MGC39372 0.383 XM_376463 1477
    TP53INP2 Tumor protein p53 inducible nuclear 0.383 NM_021202 1478
    protein 2
    GGTA1 Glycoprotein, alpha-galactosyltransferase 1 0.382 AF378123 1479
    SEQ_ID_#1480 Transcribed locus 0.381 BI757437 1480
    DUSP5 Dual specificity phosphatase 5 0.381 NM_004419 1481
    NAP1L2 Nucleosome assembly protein 1-like 2 0.381 NM_021963 1482
    HBA2 Hemoglobin, alpha 2 0.38 NM_000517 1483
    SEQ_ID_#1484 Homo sapiens, clone IMAGE: 5199401, 0.38 BC027846 1484
    mRNA
    PFN2 Profilin 2 0.38 NM_002628 1485
    GPX3 Glutathione peroxidase 3 (plasma) 0.377 NM_002084 1486
    SEQ_ID_#1487 CDNA FLJ14188 fis, clone NT2RP2005980 0.376 AK024250 1487
    PKIB Protein kinase (cAMP-dependent, 0.373 NM_032471 1488
    catalytic) inhibitor beta
    DHRS1 Dehydrogenase/reductase (SDR family) 0.372 NM_138452 1489
    member 1
    AMFR Autocrine motility factor receptor 0.371 NM_001144 1490
    PDGFRA Platelet-derived growth factor receptor, 0.368 NM_006206 1491
    alpha polypeptide
    TSPAN7 Tetraspanin 7 0.367 NM_004615 1492
    ARG2 Arginase, type II 0.367 NM_001172 1493
    AMACR Alpha-methylacyl-CoA racemase 0.366 NM_014324 1494
    ABLIM1 Actin binding LIM protein 1 0.363 NM_001003407 1495
    SEQ_ID_#1496 Full length insert cDNA clone ZD63G05 0.361 AF088051 1496
    CEACAM7 Carcinoembryonic antigen-related cell 0.361 NM_006890 1497
    adhesion molecule 7
    TP53I3 Tumor protein p53 inducible protein 3 0.357 NM_004881 1498
    OXR1 Oxidation resistance 1 0.356 NM_181354 1499
    NUCB2 Nucleobindin 2 0.356 NM_005013 1500
    SEQ_ID_#1501 Transcribed locus 0.356 BF508966 1501
    ATP6V1C2 ATPase, H+ transporting, lysosomal 0.356 NM_144583 1502
    42 kDa, V1 subunit C isoform 2
    C1orf71 Chromosome 1 open reading frame 71 0.355 NM_152609 1503
    SEQ_ID_#1504 Transcribed locus 0.354 BI757437 1504
    GJA1 Gap junction protein, alpha 1, 43 kDa 0.353 NM_000165 1505
    (connexin 43)
    IGSF11 Immunoglobulin superfamily, member 11 0.353 NM_001015887 1506
    PER1 Period homolog 1 (Drosophila) 0.352 NM_002616 1507
    C1orf42 Chromosome 1 open reading frame 42 0.351 NM_019060 1508
    RGC32 Response gene to complement 32 0.351 NM_014059 1509
    A2ML1 C3 and PZP-like, alpha-2-macroglobulin 0.35 NM_144670 1510
    domain containing 9
    CAB39L Calcium binding protein 39-like 0.35 NM_030925 1511
    ASAH3 N-acylsphingosine amidohydrolase 0.348 NM_133492 1512
    (alkaline ceramidase) 3
    SOSTDC1 Sclerostin domain containing 1 0.346 NM_015464 1513
    ABCG2 ATP-binding cassette, sub-family G 0.346 NM_004827 1514
    (WHITE), member 2
    AADACL2 Arylacetamide deacetylase-like 2 0.346 NM_207365 1515
    DPCR1 Diffuse panbronchiolitis critical region 1 0.346 NM_080870 1516
    C18orf25 Chromosome 18 open reading frame 25 0.343 NM_001008239 1517
    AKR1C2 Aldo-keto reductase family 1, member C2 0.342 NM_001354 1518
    (dihydrodiol dehydrogenase 2; bile acid
    binding protein; 3-alpha hydroxysteroid
    dehydrogenase, type III)
    TUBB2A Tubulin, beta 2 0.341 NM_001069 1519
    RASGEF1B RasGEF domain family, member 1B 0.341 NM_152545 1520
    CST6 Cystatin E/M 0.334 NM_001323 1521
    ARHGAP5 synonyms: p190-B, RhoGAPS; isoform a 0.331 NM_001030055 1522
    is encoded by transcript variant 1; p105
    RhoGAP; Rho GTPase-activating protein;
    p100 RasGAP-associated p105 protein;
    go_component: membrane [goid
    0016020] [evidence IEA];
    go_component: cytoplasm [goid
    0005737] [evidence TAS] [pmid
    8537347]; go_function: GTPase activity
    [goid 0003924] [evidence TAS] [pmid
    8537347]; go_function: Rho GTPase
    activator activity [goid 0005100]
    [evidence TAS] [pmid 8537347];
    go_process: cell adhesion [goid 0007155]
    [evidence TAS] [pmid 8537347];
    go_process: Rho protein signal
    transduction [goid 0007266] [evidence
    TAS] [pmid 8537347]; Homo sapiens Rho
    GTPase activating protein 5 (ARHGAP5),
    transcript variant 1, mRNA.
    C21orf81 Chromosome 21 open reading frame 81 0.329 NM_153750 1523
    CCDC6 Coiled-coil domain containing 6 0.328 NM_005436 1524
    ANKRD37 Ankyrin repeat domain 37 0.326 NM_181726 1525
    NQO1 NAD(P)H dehydrogenase, quinone 1 0.324 NM_000903 1526
    AKR1B10 Aldo-keto reductase family 1, member 0.323 NM_020299 1527
    B10 (aldose reductase)
    ATP6V0A4 ATPase, H+ transporting, lysosomal V0 0.322 NM_020632 1528
    subunit a isoform 4
    LOC339400 Hypothetical protein LOC339400 0.321 AK056431 1529
    GNA14 Guanine nucleotide binding protein (G 0.32 NM_004297 1530
    protein), alpha 14
    TFAP2B Transcription factor AP-2 beta (activating 0.319 NM_003221 1531
    enhancer binding protein 2 beta)
    C9orf58 Chromosome 9 open reading frame 58 0.318 NM_001002260 1532
    RDH12 Retinol dehydrogenase 12 (all-trans and 0.316 NM_152443 1533
    9-cis)
    BLZF1 Basic leucine zipper nuclear factor 1 0.315 NM_003666 1534
    (JEM-1)
    GRPEL2 GrpE-like 2, mitochondrial (E. coli) 0.312 NM_152407 1535
    LOC389432 Homo sapiens SAM domain containing 1 0.31 NM_001030060 1536
    (LOC389432), mRNA.
    YOD1 YOD1 OTU deubiquinating enzyme 1 0.309 NM_018566 1537
    homolog (yeast)
    ARG1 Arginase, liver 0.176 NM_000045 1538
    KRT6B Keratin 6B 0.309 NM_005555 1539
    SDR-O Orphan short-chain dehydrogenase/ 0.301 NM_148897 1540
    reductase
    BEXL1 Brain expressed X-linked-like 1 0.301 XM_043653 1541
    FAM43A Family with sequence similarity 43, 0.3 NM_153690 1542
    member A
    IL1F5 Interleukin 1 family, member 5 (delta) 0.295 NM_012275 1543
    CITED2 Cbp/p300-interacting transactivator, with 0.295 NM_006079 1544
    Glu/Asp-rich carboxy-terminal domain, 2
    FLJ10980 Hypothetical protein FLJ10980 0.295 BQ277484 1545
    RNASE7 Ribonuclease, RNase A family, 7 0.292 NM_032572 1546
    SEQ_ID_#1547 Similar to ankyrin repeat domain 20A 0.292 BC016022 1547
    DEPDC6 DEP domain containing 6 0.292 NM_022783 1548
    PADI1 Peptidyl arginine deiminase, type I 0.287 NM_013358 1549
    SEQ_ID_#1550 Full length insert cDNA clone YI40A07 0.287 AI819863 1550
    SPRR2D Small proline-rich protein 2D 0.286 NM_006945 1551
    S100A12 S100 calcium binding protein A12 0.286 NM_005621 1552
    (calgranulin C)
    GHR Growth hormone receptor 0.286 NM_000163 1553
    SEQ_ID_#1554 Homo sapiens hypothetical LOC441178 0.286 XM_379456 1554
    (LOC441178), mRNA.
    ZDHHC20 Zinc finger, DHHC-type containing 20 0.283 NM_153251 1555
    LOC115749 Hypothetical protein LOC115749 0.281 XM_056680 1556
    NGEF Neuronal guanine nucleotide exchange 0.279 NM_019850 1557
    factor
    LOC56901 NADH:ubiquinone oxidoreductase MLRQ 0.278 NM_020142 1558
    subunit homolog
    SORBS1 0.277 NM_001034954 1559
    HCG22 HLA complex group 22 0.276 XM_496804 1560
    FLJ40432 Hypothetical protein FLJ40432 0.275 NM_152523 1561
    SBSN Suprabasin 0.274 NM_198538 1562
    TNFAIP3 Tumor necrosis factor, alpha-induced 0.273 BG218400 1563
    protein 3
    ZNF101 Zinc finger protein 101 0.27 NM_033204 1564
    ZBED2 Zinc finger, BED-type containing 2 0.269 NM_024508 1565
    DDAH1 Dimethylarginine dimethylaminohydrolase 1 0.266 NM_012137 1566
    SLC16A6 Solute carrier family 16 (monocarboxylic 0.263 NM_004694 1567
    acid transporters), member 6
    SH3GL3 SH3-domain GRB2-like 3 0.262 NM_003027 1568
    SEQ_ID_#1569 Homo sapiens hypothetical LOC441178 0.259 XM_379456 1569
    (LOC441178), mRNA.
    FNDC4 Fibronectin type III domain containing 4 0.259 NM_022823 1570
    PAQR8 Progestin and adipoQ receptor family 0.255 NM_133367 1571
    member VIII
    SEQ_ID_#1572 Similar to ankyrin repeat domain 20A 0.248 AK092114 1572
    IL8RB Interleukin 8 receptor, beta 0.244 NM_001557 1573
    HIST1H2BC Histone 1, H2bc 0.243 NM_003526 1574
    RGS17 Regulator of G-protein signalling 17 0.243 NM_012419 1575
    SLURP1 Secreted LY6/PLAUR domain containing 1 0.24 NM_020427 1576
    BBOX1 Butyrobetaine (gamma), 2-oxoglutarate 0.238 NM_003986 1577
    dioxygenase (gamma-butyrobetaine
    hydroxylase) 1
    EDN3 Endothelin 3 0.229 NM_000114 1578
    MT1G Metallothionein 1G 0.228 NM_005950 1579
    LOC283824 Hypothetical protein LOC283824 0.227 BX647541 1580
    PCSK5 Proprotein convertase subtilisin/kexin 0.225 NM_006200 1581
    type 5
    SIAT2 ST6 beta-galactosamide alpha-2,6- 0.224 NM_032528 1582
    sialyltranferase 2
    SYNPO2L Synaptopodin 2-like 0.222 NM_024875 1583
    PNLIPRP3 Pancreatic lipase-related protein 3 0.221 NM_001011709 1584
    ME1 Malic enzyme 1, NADP(+)-dependent, 0.221 NM_002395 1585
    cytosolic
    TCP11L2 Hypothetical protein MGC40368 0.22 NM_152772 1586
    ZNF426 Zinc finger protein 426 0.215 NM_024106 1587
    CGNL1 Cingulin-like 1 0.214 NM_032866 1588
    MGC11324 Hypothetical protein MGC11324 0.21 NM_032717 1589
    LOC401097 Similar to LOC166075 0.207 XM_376281 1590
    KRTAP3-2 Keratin associated protein 3-2 0.204 NM_031959 1591
    TGM3 Transglutaminase 3 (E polypeptide, 0.203 NM_003245 1592
    protein-glutamine-gamma-
    glutamyltransferase)
    CRYM Crystallin, mu 0.199 NM_001014444 1593
    CTNNAL1 Catenin (cadherin-associated protein), 0.19 NM_003798 1594
    alpha-like 1
    CRYAB Crystallin, alpha B 0.189 NM_001885 1595
    UPK1A Uroplakin 1A 0.169 NM_007000 1596
    ECG2 Esophagus cancer-related gene-2 0.166 NM_032566 1597
    FLJ21511 Hypothetical protein FLJ21511 0.162 NM_025087 1598
    C1orf177 Chromosome 1 open reading frame 177 0.161 NM_152607 1599
    SEQ_ID_#1600 Homo sapiens cDNA clone 0.158 BC042588 1600
    IMAGE: 4826738.
    ALOX12 Arachidonate 12-lipoxygenase 0.157 NM_000697 1601
    HIG2 Hypoxia-inducible protein 2 0.156 NM_013332 1602
    C1orf161 Chromosome 1 open reading frame 161 0.154 NM_152367 1603
    SEQ_ID_#1604 0.152 NM_006518 1604
    FLG Filaggrin 0.147 NM_002016 1605
    SEQ_ID_#1606 Transcribed locus, weakly similar to 0.145 BM994473 1606
    XP_220549.3 PREDICTED: similar to Zinc
    finger protein 287 (Zfp-287) (Zinc finger
    protein SKAT-2) [Rattus norvegicus]
    MT1M Metallothionein 1K 0.129 NM_176870 1607
    P11 26 serine protease 0.125 NM_006025 1608
    NP Nucleoside phosphorylase 0.113 NM_000270 1609
    CRISP2 Cysteine-rich secretory protein 2 0.106 NM_003296 1610
    ZNF365 Hypothetical protein LOC283045 0.106 NM_014951 1611
    CLDN10 Claudin 10 0.0968 NM_006984 1612
    CDA Cytidine deaminase 0.0876 NM_001785 1613
    EPB41L3 Erythrocyte membrane protein band 4.1- 0.0832 NM_012307 1614
    like 3
    SFTPG GSGL541 0.0709 NM_205854 1615
    SNX19 Sorting nexin 19 0.0664 NM_014758 1616
    GYS2 Glycogen synthase 2 (liver) 0.0535 NM_021957 1617
    DSG1 Desmoglein 1 0.0405 NM_001942 1618
    CRISP3 Cysteine-rich secretory protein 3 0.039 NM_006061 1619
    SEQ_ID_#1620 CDNA FLJ43417 fis, clone OCBBF2026025 0.0268 AK125406 1620
  • These 1620 genes comprised an EE transcript signature, also termed an EE transcriptome. The most induced transcript in EE was eotaxin-3; levels of eotaxin-3 strongly correlated with disease severity.
  • In one embodiment, the EE transcriptome was used to evaluate EE patients pre- and post-treatment regimens. For example, corticosteroids are frequently administered to patients with EE, and the specific glucocorticoid fluticasone propionate has been shown to induce EE disease remission (Gastroenterology 131 (2006) 1381) and to reverse EE gene dysregulation (J. Allergy Clin. Immunol., 120 (2007) 1292; U.S. Application Ser. No. 61/118,981, filed Dec. 1, 2008), each of which is incorporated by reference herein in its entirety.
  • As shown in FIG. 6, treatment of EE patients with fluticasone propionate normalized greater than 99% of the EE transcriptome (1605 genes/1620 genes), while leaving less than 1% of the EE transcriptome (13 genes/1620 genes) resistant to fluticasone propionate treatment. This group of 13 non-responsive genes is SEQ ID NOS. 6, 35, 43, 61, 129, 1358, 1441, 1515, 1538, 1584, 1615, 1618, and 1620. Evaluation of these genes provides a marker of past, present, and/or future active disease, especially in the absence of overt disease. These 13 genes were resistant to therapy, however, therapy resulted in normal clinical and/or physical characteristics. Thus, these 13 genes can be used to evaluate a patient's propensity to EE, particularly in the absence of clinical or physical symptoms of EE or microscopic findings typical of EE. Because the profiles of these genes, i.e., whether they were over-expressed or under-expressed, did not change when the patient was on therapy, these 13 genes can be used to evaluate whether a patient had EE in the past or currently has inactive EE. These 13 genes can be used to evaluate EE in an asymptomatic population or when past EE is suspected in a non-active EE individual at the time of endoscopy. In one embodiment, the expression level of at least one of these 13 genes is compared to control levels and under- or over-expression of one or more of these 13 genes by ≧1.5 fold, indicating that the patient is either a past EE patient and/or is susceptible to future EE disease development.
  • The method may evaluate treatment efficacy with different drugs within a particular group (e.g., different corticosteroids), among the same group (e.g., corticosteroids compared to non-corticosteroids), or among different groups (e.g., steroids compared to non-steroid drugs). The method may evaluate treatment efficacy at different doses, provided in different therapeutic regimens (e.g., frequency, duration, etc.).
  • Normalization of expression levels of 99% of the genes in the EE transcriptome by fluticasone propionate treatment permitted determination of potential pathways by which fluticasone propionate and other treatments, e.g., other glucocorticoids, treat EE. In one embodiment, the EE transcriptome was used to examine the cellular and molecular pathways of EE, and the way by which a particular therapy treated EE, provided information about the basis, attributes, and potential modifiers of EE. For example, a role of interleukin 13 (IL-13) and its signaling pathways has been implicated in the pathophysiology of EE, as described in U.S. Application Ser. No. 61/118,981, filed Dec. 1, 2008, which is incorporated by reference herein in its entirety.
  • The 1620 genes in the EE transcriptome are highly conserved. Their complex expression pattern delineates molecular features, cell composition, and cell activation in EE.
  • In one embodiment, the EE transcriptome was compared to transcriptomes in cell/tissues that had been treated with one or more compounds potentially involved with and/or efficacious against EE. By comparing the EE transcriptome to the transcriptome of, e.g., a simple in vitro or ex vivo model of a particular compound, one can assess the percentage of genes that are dysregulated in EE due to that particular compound.
  • For example, in ex vivo or in vitro models, a compound was used to stimulate an esophageal cell type. The genes that were dysregulated in this model, and hence exhibit an altered transcriptome, allowed one to determine the percentage of genes that were dysregulated in EE due to treatment with this compound. A transcriptome generated in esophageal epithelial cells that had been stimulated with IL-13 revealed that 20% of the genes of the EE transcriptome were potentially due to IL-13 stimulation of esophageal epithelial cells. These data permitted determination of the involvement of a compound in EE, e.g. that IL-13 was a key component in EE. These data permitted assessment of the percentage of gene(s) a compound would potentially block, e.g. that an inhibitor of the compound IL-13 would potentially reverse the expression of this same 20% of the EE transcriptome and predict the potential positive effect of the compound. These data permitted generation of a list of genes that would be expected to be down-regulated by a compound, and that thus could be used to assess the compound's efficacy on therapy and/or treatment compliance.
  • In one embodiment, evaluation of the EE transcriptome was used to determine efficacy of non-drug therapies. For example, having patients with EE follow a controlled diet, where some foodstuffs are limited or eliminated, normalized expression levels of many genes in the EE transcriptome, as shown in FIG. 6. Elimination diets that completely eliminate certain foodstuffs (e.g., wheat, soy, milk, peanuts, and/or seafood) and elemental diets that completely lack certain elements (e.g., liquid diets that contain only amino acids but no proteins to act as allergens) have been used with some success to treat children with EE. In one embodiment, the EE transcriptome is used to assess potential non-drug EE treatments by comparing the gene expression profile pre- and post-such treatment. For example, a child with EE may be put on an elimination diet for a defined period, and the gene expression profile compared before, during, and at the termination of the defined period to assess effect of the foodstuff that was eliminated from the child's diet during the period.
  • Some individuals with EE do not respond to treatment (FIG. 5). Even after they have received treatment (e.g., a particular drug, elimination diet, elemental diet, etc.), such non-responder individuals have an EE transcriptome that resembles untreated EE patients, i.e., genes that are up-regulated in EE and genes that are down-regulation in EE remain up-regulated and down-regulated, respectively, despite the individual having received a particular treatment for EE.
  • Analysis of the gene expression profile pre- and post-treatment allows a medical practitioner to determine whether a particular treatment method demonstrates efficacy, or whether an alternative form of treatment, or a different treatment regime (e.g., increased dosing) is warranted. In one embodiment, analysis of the EE transcriptome is used to assess whether a patient is responding to a particular treatment.
  • In one embodiment, analysis of the EE transcriptome is used to assess and/or monitor patient compliance. For example, a patient with EE may not respond to therapy because the patient is a non-responder, or may not respond to therapy because the patient is not complying with the complete dosage regimen and thus may have a subthreshold drug concentration.
  • In one embodiment, evaluation of the EE transcriptome was used to assess EE in the presence of another pathology that may confound the diagnosis of EE. While EE is commonly diagnosed using histological methods to assess the level of eosinophil infiltration into, and/or thickening of, esophageal tissue, the presence and extent of eosinophil infiltration can be affected by various factors. The esophagus is normally devoid of eosinophils. However eosinophils can infiltrate the esophagus in pathological condition such as parasitic infection, fungal infections, hypereosinophilic syndromes, inflammatory bowel disease, certain cancers, recurrent vomiting, gastroesophageal reflux disease (GERD), etc., in addition to EE, so eosinophil presence/concentration in the esophagus cannot definitively diagnose between, e.g., EE and GERD. These diseases need to be ruled out before EE can be diagnosed. Evaluation of the EE transcriptome to identify the genes specifically involved in EE, e.g., eotaxin-3, allows one to discriminate between these pathologies and rule in or rule out EE with enhanced definiteness.
  • The diagnosis of EE is often suspected whenever dysphagia for solid food occurs, although it is not one of the more common causes of dysphagia. Dysphagia is frequently evaluated with endoscopy (esophagogastroduodenoscopy, or EGD) to determine its cause. During EGD, a flexible viewing tube or endoscope is inserted through the mouth and into the esophagus, permitting the medical practitioner to see the inner esophageal mucosa and lumen. Certain abnormalities, such as narrowing of most of the esophagus, or a series of rings along the entire length of the esophagus, suggest EE. However, in many patients with EE, upon such visualization the esophagus appears normal or shows only minor abnormalities. Thus, an accurate diagnosis of EE using visual and/or histological methods depends on the presence of characteristics that may or may not be present. The accurate diagnosis of EE using histological evaluation of a tissue biopsy specimen depends on when the biopsy is obtained. For example, histological evaluation may differ in early-stage EE biopsy tissue compared to later-stage biopsy EE tissue. The accurate diagnosis of EE may be compromised if other pathologies are present. Evaluation of the EE transcriptome permitted a more accurate assessment, diagnosis, determination of course, etc., of EE. Evaluation of the EE transcriptome may be performed independent of, or concomitant with, other assessment methods such as, e.g., histological evaluation of a tissue biopsy specimen. Evaluation of the EE transcriptome may be performed, e.g., when eosinophil infiltration has not reached pre-determined numbers, in disease remission, in the absence of physical characteristics, or in the presence of one or more confounding pathologies.
  • In one embodiment, evaluation of the EE transcriptome is used to diagnose past, present, and/or future EE disease. When a patient with EE patient is treated successfully and, upon histological evaluation of a tissue biopsy specimen, presents no pathology, the pathologist, based upon the microscopic appearance, typically reports the patient as normal with no diagnosis abnormality. However, evaluation of the EE transcriptome reveals dysregulation of the 13 non-responsive genes despite the normal histological appearance of biopsy tissues. Thus, while eosinophil tissue infiltration is a marker of active EE, evaluation of the EE transcriptome provides information of EE history, e.g., it can assess presence and/or severity of prior pathology. Such assessment is useful because the dynamic and seasonal nature of EE is known.
  • In one embodiment, evaluation of the EE transcriptome is used to diagnose EE in the absence of overt disease, i.e., EE variability and/or inherency. In one embodiment, the expression level of the 13 non-responsive genes is used to diagnose EE in the absence of overt or active disease. In one embodiment, the 13 non-responsive genes allow diagnosis of chronic and relapsing forms of EE, and may provide an understanding of the pathophysiology of these forms. For example, evaluation of the EE transcriptome can identify sporadic, e.g. recurring or relapsing, forms of EE. As described above, histological assessment of a tissue biopsy specimen and extent of tissue eosinophil infiltration depends on when, during the course of EE, the assessment is performed. In contrast, a sporadic form of EE that is missed by these methods would, in fact, be captured by evaluating the EE transcriptome because the under-expression or over-expression exhibited by these genes is independent of active EE.
  • In one embodiment, evaluation of the EE transcriptome is used to assess familial components or contributions to EE by providing a transcriptome basis of comparison among genetic family members of the EE patient. There is evidence indicating a strong familial association or aggregation for EE. Approximately 10% of parents of EE patients have a history of esophageal strictures, and approximately 8% of these have EE as established by histological evaluation of a tissue biopsy specimen.
  • Among the approximately 300 first pediatric probands, e.g. individuals exhibiting EE, recruited into our research databank, 26 of them have at least one sibling or parent with EE (data not provided). Three adult brothers with dysphagia were reported to have EE (Patel and Falchuk). One widely used measure of familial aggregation is the sibling recurrence risk ratio, termed λS, that compares the risk of sibling disease recurrence versus the risk, or disease prevalence, in the general population. A value for λS>1 indicates an increased risk of EE development among siblings of the proband, compared to the general population. The prevalence of EE in the general population is approximately 5/10,000. Based on this prevalence, the estimated sibling recurrence risk ratio, λS, for EE is approximately 80. Compared with common allergic disorders, such as atopy or asthma where λS is estimated at approximately 2, the considerably high sibling recurrence risk ratio in EE indicated that genetics was likely to have a relatively large role.
  • In one embodiment, evaluation of the EE transcriptome is used to identify candidate genes responsible for a familiar association. The gene for eotaxin-3 gene was one candidate gene. A single nucleotide polymorphism (SNP), +2496 T>G, rs2302009) in the gene for eotaxin-3 showed association with EE by both population-based case-control comparison and family-based transmission disequilibrium testing. Thus, the evaluation of the EE transcriptome among genetic family members, some of who exhibited symptoms of EE, may provide early EE diagnosis in other family members who did not exhibit symptoms. Such information facilitates determination of hereditary factors for EE.
  • In one embodiment, a diagnostic assay for eosinophilic esophagitis includes an ELISA (enzyme linked immunosorbent assay) or other clinically applicable immunoassay. In another embodiment, a diagnostic assay for eosinophilic esophagitis includes a test strip containing an anti-eotaxin-3 binding substance such as an antibody to which eotaxin-3 or eotaxin-3 like protein or peptide in a patient's biological sample (e.g. blood, sputum, feces, tissue fluid, cerebrospinal fluid, etc.) would bind. The test strip may include a chromogenic, fluorogenic, or luminescent substrate, detection reagents, etc., as known to one skilled in the art. The anti-eotaxin-3 antibody may be a rodent or other animal antieotaxin-3 antibody. The assay would include at least one suitable reagent, such as an enzyme (e.g. an oxidoreductase, transferase, hydrolase, lyase, isomerase, or ligase), in one embodiment horseradish peroxidase, o-toluidine, or colloidal gold, whereby the reagent reacts with an antigen/antibody complex on the test strip. A chromogen or other detectable indicator of binding or lack of binding, depending upon the assay format (e.g. competitive, non-competitive, sandwich, etc.) indicates binding of the anti-eotaxin-3 antibody to eotaxin-3 present in a supranormal level for a qualitative test, and may indicate the degree of binding for a quantitative or semi-quantitative test. Binding typically is indicated or visually detected via the presence or absence of color, fluorescence, luminescence, etc. Such test kit components and configurations are well known to one skilled in the art and are within the scope of the invention. An example of certain suitable substrates and a suitable reagent may include, respectively, dimethyl or diethyl analogues of p-phenylenediamine with 4-chloro-1-naphthol or 3-methyl-2-benzothiazoline hydrazone with 4-chloro-1-naphthol and horseradish peroxidase. Other exemplary substrates used with horseradish peroxidase include 3,3′,5,5′-tetramethylbenzidine, 2,2′-azinobis[3-ethylbenzothiazoline-6-sulfonic acid]-diammonium salt, o-phenylenediamine dihydrochloride, and QuantaBlu.
  • The anti-eotaxin-3 antibody may be a monoclonal or polyclonal antibody. Methods of producing monoclonal and polyclonal antibodies are known to one skilled in the art. Anti-eotaxin-3 antibodies may be generated as disclosed in U.S. Pat. No. 6,780,973, previously expressly incorporated by reference herein in its entirety. Also, a commercially available anti-eotaxin-3 antibody may be used. As indicated above, eotaxin-3 selectively signals through the CCR3 receptor expressed on activated eosinophils or on other cells such as mast cells. As such, eosinophilic esophagitis may be mitigated by altering an eotaxin-3 binding and/or signaling mechanism, and/or CCR3 structure, function, and/or internalization. One such example is a method to provide an inhibitor to eotaxin-3 and/or CCR3 in an eosinophil or a mast cell under conditions sufficient to inhibit eotaxin-3 binding to the receptor. For example, the inhibitor may be provided to the esophageal tissue or to the blood stream in an amount sufficient to inhibit eotaxin-3 binding to the eotaxin-3 receptor. The inhibitor may be a small molecule inhibitor and/or a CCR3 antagonist. Exemplary CCR3 antagonists may include a humanized or human antieotaxin-3 antibody, MIG, I-TAO, IP-10 (U.S. patent application Ser. No. 10/752,659, titled “Cytokine Inhibition of Eosinophils,” filed on Jan. 1, 2004; Zimmermann et al., J. Allergy Clin. Immunol., (2003) 3, 227), vMIP-II (Kleidel et al., Science, (1997) 277, 1656), met-RANTES (Elsner et al., Eur. J. Immunol., (1997) 27, 2892), carboxamide derivatives (Naya et al., Bioorg. Med. Chem. Lett., (2001) 11, 1219), 2-(Benzothiazolylthio)acetamide derivatives (Naya et al., Chem. Pharm. Bull., (2003) 51, 697; Saeki et al., Biochem. Biophys. Res. Comm., (2001) 281, 779), piperidine derivatives including indolinopiperidines or benzylpiperidines (Wacker et al., Bioorg. Med. Chem. Leit., (2002)12, 1785; Varnes et al., Bioorg. Med. Chem. Lett., (2004) 14, 1645), or such other nonpeptides as UCB35625 and derivatives thereof (Sabroe et al., J. Biol. Chem., (2000) 275, 25985), and SK&F-L-45523 and derivatives thereof (White et al., J. Biol. Chem., (2000) 275, 36626). Certain of the above antagonists, e.g., UCB35625, may also be considered small molecule inhibitors (Sabroe et al., J. Biol. Chem., (2000) 275, 25985). Each of the references cited is expressly incorporated by reference herein in its entirety.
  • The inhibitor need not completely inhibit binding, signal transduction, and/or function or cause receptor internalization. As used herein, an inhibitor may cause any reduction in one or more of these properties compared to a normal level. An eotaxin-3 and/or CCR3 inhibitor may also specifically inhibit transcription and/or translation of eotaxin-3, and/or CCR3 such as by utilizing antisense oligonucleotides and transcription factor inhibitors. An inhibitor may include a glucocorticoid that can work by inhibiting eotaxin-3 promoter-driven reporter gene activity and accelerating the decay of eotaxin-3 mRNA (Zimmermann et al., J. Allergy Clin. Immunol., (2003) 3, 227). An inhibitor may also induce CCR3 internalization (Zimmermann et al., J. Biol. Chem., (1999) 274, 12611). Each of the references cited is expressly incorporated by reference herein in its entirety. An inhibitor may be administered directly or with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the inhibitor to patients with, or presymptomatic for, eosinophilic esophagitis. Any appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intranasal, aerosol, or oral administration. Therapeutic formulations may be in the form of solids, liquid solutions, or suspensions; for oral administration, formulations may be in the form of tablets (chewable, dissolvable, etc.), capsules (hard or soft gel), pills, syrups, elixirs, emulsions, etc.; and for intranasal formulations, in the form of powders, nasal drops, or aerosols. In one embodiment, a CCR3 antagonist is administered parenterally and/or orally. Enteral formulations may contain thixotropic agents, flavoring agents, and other ingredients for enhancing organoleptic qualities.
  • Methods known in the art for making formulations are found in, for example, “Remington's Pharmaceutical Sciences.” Formulations for parenteral administration may, for example, contain excipients, including but not limited to pharmaceutically acceptable buffers, emulsifiers, surfactants, and electrolytes such as sodium chloride, as well as sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Formulations for inhalation may also contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • Applicants incorporate by reference the material contained in the accompanying computer readable Sequence Listing identified as SEQUENCE_LISTING_ST25.txt, having a file creation date of Jun. 24, 2009 3:30 P.M. and a file size of 6.98 MB.
  • Other variations or embodiments of the invention will also be apparent to one of ordinary skill in the art from the above figures and descriptions. Thus, the forgoing embodiments are not to be construed as limiting the scope of this invention.

Claims (7)

1. A method to evaluate an individual's propensity for eosinophilic esophagitis (ee), the method comprising
determining an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in an esophagus of an individual,
comparing the expression profile of the at least one gene of the individual with an expression profile from an individual without EE,
evaluating the individual's propensity for EE by determining if the at least one gene is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile from the individual without EE, and
ranking the individual's propensity for EE based on at least one of
(a) the extent that over-expression or under-expression exceeds 1.5,
(b) the identify of the gene over-expressed or under-expressed, or
(c) the number of genes that are over-expressed or under-expressed, where the individual has a higher propensity for EE when (a) is farther from 1.5, (b) is selected from the group consisting of SEQ ID NOS. 1-42, and (c) is farther from 1.
2. The method of claim 1 wherein (b) is SEQ ID NO. 1.
3. The method of claim 1 wherein the individual lacks at least one of clinical and physical symptoms of EE.
4. A method to evaluate a compound's contribution to the pathophysiology of eosinophilic esophagitis (EE), the method comprising
exposing at least one cell to the compound,
comparing an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in the at least one cell to an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 1-1620 in a cell of an individual without EE,
evaluating the contribution of the compound to the pathophysiology of EE by determining if the at least one gene in the cell is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile of the individual without EE, and
ranking the compound's contribution to the pathophysiology of EE based on at least one of
(a) the extent that over-expression or under-expression exceeds 1.5,
(b) the identify of the gene over-expressed or under-expressed, or
(c) the number of genes that are over-expressed or under-expressed, where the compound contributes more to the pathophysiology of EE when (a) is farther from 1.5, (b) is selected from the group consisting of SEQ ID NOS. 1-42, and (c) is farther from 1.
5. The method of claim 4 wherein the cell is an esophageal cell.
6. A method to evaluate whether an individual had prior eosinophilic esophagitis (EE), the method comprising
determining an expression profile of at least one gene selected from the group consisting of SEQ ID NOS. 6, 35, 43, 61, 129, 1358, 1441, 1515, 1538, 1584, 1615, 1618, and 1620 in an esophagus of an individual,
comparing the expression profile of the at least one gene of the individual with an expression profile from an individual without EE,
evaluating whether the individual had prior EE by determining if the at least one gene is either over-expressed ≧1.5 times or is under-expressed ≧1.5 times compared to the same gene in the expression profile from the individual without EE, and
ranking the likelihood that the individual had prior EE based on at least one of
(a) the extent that over-expression or under-expression exceeds 1.5, or
(b) the number of genes that are over-expressed or under-expressed, where the individual is more likely to have had EE when (a) is farther from 1.5, and (b) is farther from 1.
7. The method of claim 6 where the individual does not have active EE.
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US10155985B2 (en) 2018-12-18
US20090233275A1 (en) 2009-09-17
US20110195500A1 (en) 2011-08-11

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