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WO2013080227A1 - Variants génétiques utiles pour l'évaluation du risque de maladie artérielle - Google Patents

Variants génétiques utiles pour l'évaluation du risque de maladie artérielle Download PDF

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WO2013080227A1
WO2013080227A1 PCT/IS2012/050015 IS2012050015W WO2013080227A1 WO 2013080227 A1 WO2013080227 A1 WO 2013080227A1 IS 2012050015 W IS2012050015 W IS 2012050015W WO 2013080227 A1 WO2013080227 A1 WO 2013080227A1
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allele
subject
coronary artery
disease
condition
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Anna Helgadottir
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Decode Genetics ehf
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Decode Genetics ehf
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    • 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
    • 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
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • CAD Coronary Artery Disease
  • MI Myocardial Infarction
  • AAA Abdominal Aortic Aneurysm
  • PPD Peripheral Arterial Disease
  • the identified loci may for example promote the initiation of coronary atheroma, the progression of atherosclerotic plaques, increase susceptibility of plaque rupture, or faciltate arterial thrombosis, thus leading to the observed phenotype.
  • knowledge about genetic variation that confers risk of these diseases may provide valuable information about their etiology.
  • the present invention discloses the utility of certain genetic variants in lipoprotein (a) (Lp(a)) in the risk management of certain vascular conditions.
  • the present inventors have discovered that certain genetic variants in the human LPA gene are associated with risk of arterial conditions such as large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease. These variants are useful in diagnostic methods and related aspects, as described in detail herein.
  • the invention provides a method of determining a susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a human subject, the method comprising analyzing data representative of at least one allele of a polymorphism selected from the group consisting of rs3798220 and rsl0455872 in the subject, wherein the presence of allele C in rs3798220 and/or allele G in rsl0455872 is associated with increased susceptibility to the condition in humans, and determining a susceptibility to the condition for the human subject from the data.
  • the invention also provides a method of determining whether a human subject is at increased risk of developing a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease, the method comprising steps of (i) obtaining a biological sample containing nucleic acid from the subject; and (ii) determining, in the biological sample, the allelic identity of at least one polymorphic marker selected from rs3798220 and rsl0455872;
  • identification of at least one allele selected from allele C in rs3798220 and allele G in rsl0455872 in the biological sample is indicative that the subject is at increased risk of developing the condition.
  • a method of determining a susceptibility to severe coronary artery disease in a human subject comprising analyzing data representative of at least one allele of a polymorphism selected from the group consisting of rs3798220 and rsl0455872 in the subject, wherein the presence of allele C in rs3798220 and allele G in rsl0455872 is associated with increased number of obstructed coronary artery in humans, and determining a susceptibility to severe coronary artery disease for the human subject from the data.
  • the invention also provides an assay for determining a susceptibility to a condition selected from the group consisting of abdominal aortic aneurysm, peripheral arterial disease, large arterial atherosclerosis, early-onset coronary artery disease and severe coronary artery disease in a human subject, the assay comprising steps of (i) obtaining a biological sample comprising nucleic acid from the subject; (ii) determining, in the nucleic acid, the presence or absence of at least one allele of a polymorphism selected from the group consisting of rs3798220 and rsl0455872, wherein the presence of allele C in rs3798220 and allele G in rsl0455872 is associated with increased susceptibility to the condition in humans; and (iii) determining a susceptibility to the condition for the subject from the presence or absence of the at least one allele.
  • a condition selected from the group consisting of abdominal aortic aneurysm, peripheral arterial disease, large arterial athe
  • the invention also relates to prognosis.
  • the invention provides a method of determining the prognosis of a human subject diagnosed with coronary artery disease, the method comprising steps of (i) obtaining a biological sample containing nucleic acid from the subject; and (ii) determining, in the biological sample, the allelic identity of at least one polymorphic marker selected from rs3798220 and rsl0455872; wherein identification of at least one allele selected from allele C in rs3798220 and allele G in rsl0455872 in the biological sample is indicative of a worse prognosis of the coronary artery disease for the subject.
  • One such aspect relates to a system for identifying susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early- onset coronary artery disease and severe coronary artery disease, the system comprising (i) at least one processor; (ii) at least one computer-readable medium; (iii) a susceptibility database operatively coupled to a computer-readable medium of the system and containing population information correlating the presence or absence of one or more alleles selected from allele C in rs3798220 and allele G in rsl0455872 to susceptibility of the condition in a population of humans; (iv) a measurement tool that receives an input about the human subject and generates information from the input about the presence or absence of the at least one allele in the human subject; and (v) an analysis tool that (a) is operatively coupled to the susceptibility database and the measurement tool; (
  • FIG 1 provides a diagram illustrating a system comprising computer implemented methods utilizing risk variants as described herein.
  • FIG 2 shows an exemplary system for determining risk of vascular conditions as described further herein.
  • FIG 3 shows a system for selecting a treatment protocol for a subject diagnosed with a vascular condition.
  • FIG 4 demonstrates association of LPA score (markers rs3798220 and rsl0455872) with vascular diseases.
  • Combined odds ratios (OR) from multiple studies are indicated by square, with an area in proportion to the sample size, and horizontal lines representing the 95% confidence intervals (CI) .
  • FIG 5 demonstrates the association of LPA score with CAD, with and without atherosclerosis in other vascular territories, and with age-group at onset of CAD.
  • the P-value contrasting the two groups of CAD cases is shown (P*) .
  • B) is a forest plot of the association of LPA score with early onset of CAD (diagnosed before the age of 50 in men and 60 in women), intermediate onset
  • FIG 6 shows the distribution of the number of coronary vessels with > 50% stenosis according to LPA score is shown in the boxplots A - C.
  • the boxes represent the
  • N number of subjects.
  • nucleic acid sequences are written left to right in a 5' to 3' orientation.
  • Numeric ranges recited within the specification are inclusive of the numbers defining the range and include each integer or any non-integer fraction within the defined range.
  • all technical and scientific terms used herein have the same meaning as commonly understood by the ordinary person skilled in the art to which the invention pertains.
  • the marker can comprise any allele of any variant type found in the genome, including SNPs, mini- or microsatellites, translocations and copy number variations (insertions, deletions, duplications) .
  • Polymorphic markers can be of any measurable frequency in the population. For mapping of disease genes, polymorphic markers with population frequency higher than 5- 10% are in general most useful. However, polymorphic markers may also have lower population frequencies, such as 1-5% frequency, or 0. 1- 1% frequency, or even lower frequency. The term shall, in the present context, be taken to include polymorphic markers with any population frequency.
  • an “allele” refers to the nucleotide sequence of a given locus (position) on a chromosome.
  • a polymorphic marker allele thus refers to the composition (i.e. , sequence) of the marker on a chromosome.
  • CEPH sample (Centre d'Etudes du Polymorphisme Humain, genomics repository, CEPH sample 1347-02) is used as a reference, the shorter allele of each microsatellite in this sample is set as 0 and all other alleles in other samples are numbered in relation to this reference.
  • allele 1 is 1 bp longer than the shorter allele in the CEPH sample
  • allele 2 is 2 bp longer than the shorter allele in the CEPH sample
  • allele 3 is 3 bp longer than the lower allele in the CEPH sample
  • allele -1 is 1 bp shorter than the shorter allele in the CEPH sample
  • allele -2 is 2 bp shorter than the shorter allele in the CEPH sample, etc.
  • Sequence conucleotide ambiguity as described herein is as proposed by IUPAC-IUB. These codes are compatible with the codes used by the EMBL, GenBank, and PIR databases.
  • a nucleotide position at which more than one sequence is possible in a population is referred to herein as a "polymorphic site”.
  • a "Single Nucleotide Polymorphism” or "SIMP” is a DNA sequence variation occurring when a single nucleotide at a specific location in the genome differs between members of a species or between paired chromosomes in an individual. Most SNP polymorphisms have two alleles. Each individual is in this instance either homozygous for one allele of the polymorphism (i.e. both chromosomal copies of the individual have the same nucleotide at the SNP location), or the individual is heterozygous (i.e. the two sister chromosomes of the individual contain different nucleotides).
  • SNP nomenclature sometimes refers to the official Reference SNP (rs) ID identification tag as assigned to each unique SNP by the National Center for Biotechnological Information (NCBI).
  • NCBI National Center for Biotechnological Information
  • a “variant”, as described herein, refers to a segment of DNA that differs from the reference DNA.
  • a “marker” or a “polymorphic marker”, as defined herein, is a variant. Alleles that differ from the reference are referred to as “variant” alleles. A “variant” is sometimes also referred to as a “mutant”.
  • a "microsatellite” is a polymorphic marker that has multiple small repeats of bases that are 2-8 nucleotides in length (such as CA repeats) at a particular site, in which the number of repeat lengths varies in the general population.
  • An “indel” is a common form of
  • polymorphism comprising a small insertion or deletion that is typically only a few nucleotides long.
  • haplotype refers to a segment of genomic DNA that is characterized by a specific combination of alleles arranged along the segment.
  • a haplotype comprises one member of the pair of alleles for each polymorphic marker or locus along the segment.
  • the haplotype can comprise two or more alleles, three or more alleles, four or more alleles, or five or more alleles.
  • susceptibility refers to the proneness of an individual towards the development of a certain state (e.g., a certain trait, phenotype or disease), or towards being less able to resist a particular state than the average individual.
  • the term encompasses both increased susceptibility and decreased susceptibility.
  • particular alleles at polymorphic markers of the invention as described herein may be characteristic of increased susceptibility (i.e., increased risk) of a vascular condition as described herein, as characterized by a relative risk (RR) or odds ratio (OR) of greater than one for the particular allele.
  • the markers of the invention are characteristic of decreased susceptibility (i.e., decreased risk) of the condition, as characterized by a relative risk of less than one.
  • look-up table is a table that correlates one form of data to another form, or one or more forms of data to a predicted outcome to which the data is relevant, such as phenotype or trait.
  • a look-up table can comprise a correlation between allelic data for at least one polymorphic marker and a particular trait or phenotype, such as a particular disease diagnosis, that an individual who comprises the particular allelic data is likely to display, or is more likely to display than individuals who do not comprise the particular allelic data.
  • Look-up tables can be multidimensional, i.e. they can contain information about multiple alleles for single markers simultaneously, or they can contain information about multiple markers, and they may also comprise other factors, such as particulars about diseases diagnoses, racial information, biomarkers, biochemical measurements, therapeutic methods or drugs, etc.
  • a "computer-readable medium” is an information storage medium that can be accessed by a computer using a commercially available or custom-made interface.
  • Exemplary computer- readable media include memory (e.g., RAM, ROM, flash memory, etc.), optical storage media (e.g., CD-ROM), magnetic storage media (e.g., computer hard drives, floppy disks, etc.), punch cards, or other commercially available media.
  • Information may be transferred between a system of interest and a medium, between computers, or between computers and the computer-readable medium for storage or access of stored information. Such transmission can be electrical, or by other available methods, such as IR links, wireless connections, etc.
  • nucleic acid sample refers to a sample obtained from an individual that contains nucleic acid (DNA or RNA).
  • the nucleic acid sample comprises genomic DNA.
  • a nucleic acid sample can be obtained from any source that contains genomic DNA, including a blood sample, sample of amniotic fluid, sample of cerebrospinal fluid, or tissue sample from skin, muscle, buccal or conjunctival mucosa, placenta, gastrointestinal tract or other organs.
  • antisense agent or “antisense oligonucleotide” refers, as described herein, to molecules, or compositions comprising molecules, which include a sequence of purine an pyrimidine heterocyclic bases, supported by a backbone, which are effective to hydrogen bond to a corresponding contiguous bases in a target nucleic acid sequence.
  • the backbone is composed of subunit backbone moieties supporting the purine and pyrimidine hetercyclic bases at positions which allow such hydrogen bonding. These backbone moieties are cyclic moieties of 5 to 7 atoms in size, linked together by phosphorous-containing linkage units of one to three atoms in length.
  • the antisense agent comprises an oligonucleotide molecule.
  • Lp(a) refers to lipoprotein(a).
  • the Lp(a) protein is encoded by the lipoprotein(a) gene, which is referred to herein as "LPA”.
  • systemic atherosclerotic disease refers to atherosclerotic disease that affects multiple (at least two) regional circulations, including heart, brain, kidneys, limbs, and mesentery.
  • variants in the human lipoprotein a gene ⁇ LPA are predictive of risk of vascular conditions and severity of cardiovascular disease.
  • Lipoprotein structure is similar to plasminogen and tPA (tissue plasminogen activator) and it has been shown to affect (reduce) fibrinolysis and (increase) thrombogenesis.
  • tPA tissue plasminogen activator
  • the LDL cholesterol content of Lp(a) contributes to atherosclerosis.
  • High LPA levels in blood has been shown to be a risk factor for coronary heart disease (CHD), cerebrovascular disease (CVD), atherosclerosis, thrombosis, and stroke.
  • CHD coronary heart disease
  • CVD cerebrovascular disease
  • atherosclerosis CAD
  • thrombosis CAD
  • stroke CAD
  • few reported studies have investigated the association between genetic variants that affect Lp(a) concentration and coronary artery disease.
  • the frequency of small apo(a) isoforms has been shown to be higher in patients with myocardial infarction compared with healthy controls
  • LPA variants and the number of coronary arteries (out of 4 index vessels) with > 50% stenosis, i. e. severity of CAD.
  • Lp(a) levels have an effect on the atherosclerotic burden of large vessels throughout the arterial tree.
  • genotyping LPA variants may be clinically useful, not only in determining risk for
  • LPA alleles can predict an important disease subtype, that carries an adverse prognosis. Evaluating such LPA risk alleles may therefore compliment traditional risk assessment in secondary CAD prevention as well as in primary prevention.
  • LPA risk alleles in patients may further prove important as the risk alleles may interact with therapeutic agents aimed at lowering Lp(a) levels.
  • the inventors have furthered the knowledge about the relationship between the LPA variants and CAD. Such insight into the pathogenic mechanism is important when GWAS discoveries for CAD are translated into prognostic and therapeutic tools.
  • the present invention in a first aspect provides a method of determining a susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a human subject, the method comprising analyzing data representative of at least one allele of a polymorphism selected from the group consisting of rs3798220 (SEQ ID NO: 20) and rsl0455872 (SEQ ID NO: 106) in the subject, wherein the presence of allele C in rs3798220 and/or allele G in rsl0455872 is associated with increased susceptibility to the condition in humans, and determining a susceptibility to the condition for the human subject from the data.
  • the method comprises analyzing data for at least one allele of rs3798220 and rsl0455872, wherein a determination of the presence of allele C in rs3798220 and/or allele G in rsl0455872 is associated with increased susceptibility of the condition in the human subject.
  • both alleles of markers rs3798220 and rsl0455872 are analyzed, wherein a determination of the presence of allele C in rs3798220 and/or allele G in rsl0455872 is associated with increased susceptibility of the condition in the human subject.
  • the condition is severe coronary artery disease.
  • severe coronary artery disease is a disease that is characterized by at least one of (i) at least 50% stenosis of more than one coronary artery; (ii) systemic atherosclerotic disease in the human subject, and (iii) the concomitant diagnosis of coronary artery disease and at least one of (a) abdominal aortic aneurysm; (b) peripheral arterial disease; and (c) large arterial atherosclerosis.
  • the invention provides a method of determining a susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a human subject, the method comprising analyzing data representative of at least one allele of a polymorphism selected from the group consisting of rs3798220 and
  • rsl0455872 in the subject or a polymorphism in linkage disequilibrium therewith, and determining a susceptibility to the condition for the human subject from the data.
  • determination of the presence of an allele of the at least one polymorphism that is associated with increased susceptibility to the condition in humans is indicative that the human subject is at increased susceptibility to the condition.
  • polymorphisms in linkage disequilibrium with rs3798220 and/or rsl0455872 are correlated with rs3798220 and/or rsl0455872 by values of the correlation coefficient r 2 > 0.2. In one preferred embodiment, polymorphisms in linkage disequilibrium with rs3798220 and/or rsl0455872 are correlated with rs3798220 and/or rsl0455872 by values of the correlation coefficient r 2 > 0.5. In one embodiment, polymorphisms correlated with rs3798220 are selected from the polymorphic markers set forth in the Surrogate Marker Table (a). In one embodiment, polymorphisms correlated with rsl0455872 are selected from the polymorphic markers set forth in the Surrogate Marker Table (b).
  • the analyzing data in certain embodiments comprises determining the allelic identity of at least one polymorphic marker.
  • the analyzing may further comprise obtaining a biological sample from the human subject.
  • a second aspect therefore provides a method of determining whether a human subject is at increased risk of developing a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease, the method comprising steps of (1) obtaining a biological sample containing nucleic acid from the subject; (2) determining, in the biological sample, the allelic identity of at least one polymorphic marker selected from rs3798220 and rsl0455872; (3) wherein identification of at least one allele selected from allele C in rs3798220 and allele G in rsl0455872 in the biological sample is indicative that the subject is at increased risk of developing the condition.
  • the data is nucleic acid sequence data.
  • Nucleic acid sequence data identifying particular alleles of polymorphic markers is sometimes also referred to as genotype data. Allelic identity of allele(s) of a polymorphic marker is sometimes also referred to as a genotype.
  • nucleic acid sequence data is obtained from a biological sample from the individual.
  • the nucleic acid sequence data can thus be sequence data obtained by analysis of a biological sample from an individual.
  • the biological sample in one embodiment is a nucleic acid sample, i.e. the sample contains nucleic acid from the individual.
  • Nucleic acid sequence data can be obtained for example by analyzing sequence of the at least one polymorphic marker in a nucleic acid sample from the individual.
  • nucleic acid sequence data can be obtained in a genotype dataset from the human individual and by analyzing sequence of the at least one polymorphic marker in the dataset. Such analysis in certain embodiments comprises determining the presence or absence of a particular allele of specific polymorphic markers.
  • the method of the invention comprises steps of (i) obtaining a nucleic acid sample from an individual; (ii) determining the nucleic acid sequence of at least one polymorphic marker in the nucleic acid sample; and (iii) determining a susceptibility to the condition from the nucleic acid sequence of the at least one polymorphic marker.
  • a further aspect of the invention relates to method for determining susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a human subject, the method comprising analyzing nucleic acid from the individual for evidence of the presence of allele C in rs3798220 and/or allele G in rsl0455872; and determining an increased susceptibility to the condition from evidence that allele C in rs3798220 and/or allele G in rsl0455872 is present in the subject, or determining a decreased susceptibility to the condition from evidence that allele C in rs3798220 and/or allele G in rsl0455872 is absent in the subject.
  • the evidence of the presence of allele C in rs3798220 and/or allele G in rsl0455872 may conveniently be obtained by assaying or detecting allele C in rs3798220 and/or allele G in rsl0455872 directly.
  • the skilled person will appreciate that it may also be convenient to obtain such evidence by assaying marker(s) that are surrogates of rs3798220 and/ rsl0455872.
  • surrogates which are markers that are in linkage disequilibrium and correlated with in rs3798220 and/or rsl0455872, provide information about rs3798220 and/or rsl0455872 through their genetic relationship.
  • the surrogate markers are in essence useful proxies for rs3798220 and/or rsl0455872, and the evidence of the presence of allele C in rs3798220 and/or allele G in rsl0455872 may be obtained by assaying for specific alleles of such surrogate markers.
  • Surrogate markers can be selected based on certain values of the linkage disequilibrium measures D' and r 2 , as described further herein.
  • linkage disequilibrium is a continuous measure
  • certain values of the LD measure r 2 may be suitably chosen to define markers that are useful as surrogate markers in LD with the markers described herein.
  • suitable markers in linkage disequilibrium are correlated with the anchor marker ⁇ i.e., rs3798220 and/or rsl0455872) by values of r 2 greater than 0.2.
  • suitable markers in linkage disequilibrium are correlated with the anchor marker by values of r 2 greater than 0.5.
  • suitable markers in linkage disequilibrium are correlated with the anchor marker by values of r 2 greater than 0.8. In one embodiment, suitable markers in linkage disequilibrium are correlated with the anchor marker by values of r 2 of 1.0. Such markers are perfect surrogates of the anchor marker, and will give identical association results, i.e. they provide identical genetic information.
  • markers that are useful in a diagnostic for determining a susceptibility to vascular conditions as described herein e.g., large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease
  • an increase in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with the condition, as compared with the frequency of the at least one allele in the control group is indicative of the at least one allele being useful for assessing increased susceptibility to the condition.
  • a decrease in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with the condition, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one allele being useful for assessing decreased susceptibility to, or protection against, the condition.
  • the T allele of rs3798220 is indicative a decreased susceptibility to the condition.
  • the G allele of rsl0455872 is indicative of a decreased susceptibility to the condition.
  • sequence data can be obtained by analyzing a sample from an individual, or by analyzing information about specific markers in a genotype database.
  • sequence data can be obtained through nucleic acid sequence information or amino acid sequence information from a preexisting record about a human individual.
  • a preexisting record can be any documentation, database or other form of data storage containing such information.
  • Determination of a susceptibility or risk of a particular individual in general comprises comparison of the genotype information (sequence information about particular marker or a plurality of markers) to a record or database providing a correlation about particular polymorphic marker(s) and susceptibility to the vascular condition.
  • determining a susceptibility comprises comparing the sequence data to a database containing correlation data between the at least one polymorphic marker and susceptibility to the condition.
  • the database comprises at least one measure of susceptibility to the condition for the at least one polymorphic marker.
  • the database comprises a look-up table comprising at least one measure of susceptibility to the condition for the at least one polymorphic marker.
  • Determination of susceptibility is based on sequence information about particular markers identifying particular alleles at those markers.
  • a calculation of susceptibility (risk) of the vascular condition is performed based on the information, using risk measures that have been determined for the particular alleles or combination of alleles.
  • the measure of susceptibility may in the form of relative risk (RR), absolute risk (AR), percentage (%) or other convenient measure for describing genetic susceptibility of individuals.
  • Another aspect of the invention relates to a method for determining a susceptibility to a condition selected from the group consisting of abdominal aortic aneurysm, peripheral arterial disease, large arterial atherosclerosis, early-onset coronary artery disease and severe coronary artery disease in a human subject, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, or in a genotype dataset from the individual, wherein the at least one polymorphic marker is selected from the group consisting of rs3798220 and rsl0455872, and wherein determination of the presence of the at least one allele is indicative of a susceptibility to the condition.
  • Determination of the presence of an allele that correlates with the condition is indicative of an increased susceptibility (increased risk) to the condition.
  • determination of the presence of an allele selected from the group consisting of allele C in rs3798220 and allele G in rsl0455872 is associated with increased susceptibility to the condition in humans. Individuals who are homozygous for these alleles are particularly susceptible to the condition. On the other hand, individuals who do not carry these at-risk alleles are at a decreased susceptibility of developing the condition. For SNPs, such individuals will be homozygous for the alternate (protective) allele of the polymorphism.
  • Determination of susceptibility is in some embodiments reported using non-carriers of the at- risk alleles of polymorphic markers as a reference. In certain embodiments, susceptibility is reported based on a comparison with the general population, e.g. compared with a random selection of individuals from the population. Such embodiments thus reflect the susceptibility (risk) of an individual compared with a randomly selected individual from the population.
  • polymorphic markers are detected by sequencing technologies. Obtaining sequence information about an individual identifies particular nucleotides in the context of a sequence. For SNPs, sequence information about a single unique sequence site is sufficient to identify alleles at that particular SNP. For markers comprising more than one nucleotide, sequence information about the genomic region of the individual that contains the polymorphic site identifies the alleles of the individual for the particular site. The sequence information can be obtained from a sample from the individual. In certain embodiments, the sample is a nucleic acid sample. In certain other embodiments, the sample is a protein sample.
  • Sequence data can be nucleic acid sequence data, which may be obtained by means known in the art. Sequence data is suitably obtained from a biological sample of genomic DNA, RNA, or cDNA (a "test sample") from an individual ("test subject). For example, nucleic acid sequence data may be obtained through direct analysis of the sequence of the polymorphic position (allele) of a polymorphic marker.
  • Suitable methods include, for instance, whole genome sequencing methods, whole genome analysis using SNP chips (e.g., Infinium HD BeadChip), cloning for polymorphisms, non-radioactive PCR-single strand conformation polymorphism analysis, denaturing high pressure liquid chromatography (DHPLC), DNA hybridization, computational analysis, single-stranded conformational polymorphism (SSCP), restriction fragment length polymorphism (RFLP), automated fluorescent sequencing; clamped denaturing gel electrophoresis (CDGE);
  • SNP chips e.g., Infinium HD BeadChip
  • DLP denaturing high pressure liquid chromatography
  • DNA hybridization computational analysis, single-stranded conformational polymorphism (SSCP), restriction fragment length polymorphism (RFLP), automated fluorescent sequencing; clamped denaturing gel electrophoresis (CDGE);
  • DGGE denaturing gradient gel electrophoresis
  • CMC chemical mismatch cleavage
  • RNase protection assays use of polypeptides that recognize nucleotide mismatches, such as E. coli mutS protein, allele-specific PCR, and direct manual and automated sequencing.
  • Exemplary technologies include 454 pyrosequencing technology (Nyren, P. et al. Anal
  • sequence data useful for performing the present invention may be obtained by any such sequencing method, or other sequencing methods that are developed or made available.
  • any sequence method that provides the allelic identity at particular polymorphic sites ⁇ e.g., the absence or presence of particular alleles at particular polymorphic sites) is useful in the methods described and claimed herein.
  • hybridization methods may be used (see Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley & Sons, including all supplements).
  • a biological sample of genomic DNA, RNA, or cDNA may be obtained from a test subject. The subject can be an adult, child, or fetus.
  • the DNA, RNA, or cDNA sample is then examined.
  • the presence of a specific marker allele can be indicated by sequence-specific hybridization of a nucleic acid probe specific for the particular allele.
  • the presence of more than one specific marker allele or a specific haplotype can be indicated by using several sequence-specific nucleic acid probes, each being specific for a particular allele.
  • a sequence- specific probe can be directed to hybridize to genomic DNA, RNA, or cDNA.
  • a "nucleic acid probe" as used herein, can be a DNA probe or an RNA probe that hybridizes to a complementary sequence.
  • One of skill in the art would know how to design such a probe so that sequence specific hybridization will occur only if a particular allele is present in a genomic sequence from a test sample.
  • determination of a susceptibility to intracranial aneurysm and abdominal aortic aneurysm comprises forming a hybridization sample by contacting a test sample, such as a genomic DNA sample, with at least one nucleic acid probe.
  • a test sample such as a genomic DNA sample
  • a probe for detecting mRNA or genomic DNA is a labeled nucleic acid probe that is capable of hybridizing to mRNA or genomic DNA sequences described herein.
  • the nucleic acid probe can be, for example, a full-length nucleic acid molecule, or a portion thereof, such as an oligonucleotide of at least 10, 15, 30, 50, 100, 250 or 500 nucleotides in length that is sufficient to specifically hybridize under stringent conditions to appropriate mRNA or genomic DNA.
  • the nucleic acid probe can comprise all or a portion of the nucleotide sequence of a sequence that comprises one of the markers described herein, or a sequence that is flanking one of the markers described herein, or the probe can be the complementary sequence of such a sequence.
  • Hybridization can be performed by methods well known to the person skilled in the art (see, e.g., Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley & Sons, including all supplements).
  • hybridization refers to specific hybridization, i.e., hybridization with no mismatches (exact hybridization).
  • the hybridization conditions for specific hybridization are high stringency.
  • the sample contains the allele that is complementary to the nucleotide that is present in the nucleic acid probe.
  • Allele-specific oligonucleotides can also be used to detect the presence of a particular allele in a nucleic acid.
  • An "allele-specific oligonucleotide” (also referred to herein as an “allele- specific oligonucleotide probe") is an oligonucleotide of any suitable size, for example an oligonucleotide of approximately 10-50 base pairs or approximately 15-30 base pairs, that specifically hybridizes to a nucleic acid which contains a specific allele at a polymorphic site (e.g., a polymorphic marker).
  • An allele-specific oligonucleotide probe that is specific for one or more particular alleles at polymorphic markers can be prepared using standard methods (see, e.g., Current Protocols in Molecular Biology, supra). PCR can be used to amplify the desired region. Specific hybridization of an allele-specific oligonucleotide probe to DNA from a subject is indicative of the presence of a specific allele at a polymorphic site (see, e.g., Gibbs et al., Nucleic Acids Res. 17: 2437-2448 (1989) and WO 93/22456).
  • arrays of oligonucleotide probes that are complementary to target nucleic acid sequence segments from a subject can be used to identify particular alleles in a nucleic acid.
  • an oligonucleotide array can be used.
  • Oligonucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. These arrays can generally be produced using mechanical synthesis methods or light directed synthesis methods that incorporate a combination of photolithographic methods and solid phase oligonucleotide synthesis methods, or by other methods known to the person skilled in the art
  • Suitable biological sample in the methods described herein can be any sample containing nucleic acid (e.g., genomic DNA) and/or protein from the human individual.
  • the biological sample can be a blood sample, a serum sample, a leukapheresis sample, an amniotic fluid sample, a cerbrospinal fluid sample, a hair sample, a tissue sample from skin, muscle, buccal, or conjuctival mucosa, placenta, gastrointestinal tract, or other organs, a semen sample, a urine sample, a saliva sample, a nail sample, a tooth sample, and the like.
  • the sample is a blood sample, a saliva sample or a buccal swab.
  • genotypes of un-genotyped relatives For every un-genotyped case, it is possible to calculate the probability of the genotypes of its relatives given its four possible phased genotypes. In practice it may be preferable to include only the genotypes of the case's parents, children, siblings, half-siblings (and the half-sibling's parents), grand-parents, grand-children (and the grand-children's parents) and spouses. It will be assumed that the individuals in the small sub-pedigrees created around each case are not related through any path not included in the pedigree. It is also assumed that alleles that are not transmitted to the case have the same frequency - the population allele frequency. The probability of the genotypes of the case's relatives can then be computed by:
  • Pr(genotypes of relatives; ⁇ ) ⁇ Pr(h; ⁇ ) Pr(genotypes of relatives I h) ,
  • ⁇ denotes the A allele's frequency in the cases. Assuming the genotypes of each set of relatives are independent, this allows us to write down a likelihood function for ⁇ :
  • the likelihood function in (*) may be thought of as a pseudolikelihood approximation of the full likelihood function for ⁇ which properly accounts for all dependencies.
  • genotyped cases and controls in a case-control association study are not independent and applying the case-control method to related cases and controls is an analogous
  • nucleic acid sequence data may be obtained through indirect analysis of the nucleic acid sequence of the allele of the polymorphic marker, i.e. by detecting a protein variation.
  • the C allele of rs3798220 encodes an isoleucing to methionine substitution in the human Lp(a) protein, at position 4399 in Lp(a) (I4399M).
  • this variant may suitably be detected through detection of the identity of the amino acid at position 4399 in an encoded Lp(a) protein.
  • variant proteins are known in the art. For example, direct amino acid sequencing of the variant protein followed by comparison to a reference amino acid sequence can be used. Alternatively, SDS-PAGE followed by gel staining can be used to detect variant proteins of different molecular weights. Also, Immunoassays, e.g., antibody assays, e.g., immunofluorescent immunoassays, immunoprecipitations, radioimmunoasays, ELISA, and Western blotting, in which an antibody specific for an epitope comprising the variant sequence among the variant protein and non-variant or wild-type protein can be used. In certain embodiments, the amino acid sequence data is obtained or deduced from a preexisting record. Number of Polymorphic Markers/Genes Analyzed
  • the methods can comprise obtaining sequence data about any number of polymorphic markers and/or about any number of genes.
  • the method can comprise obtaining sequence data for about at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 500, 1000, 10,000 or more polymorphic markers.
  • the sequence data is obtained from a microarray comprising probes for detecting a plurality of markers.
  • the sequence data is obtained through nucleic acid sequencing, for example by high-throughput nucleic acid sequencing.
  • the sequence data may also be obtained by imputation of nucleic acid sequence using known methods, such as those described herein.
  • the polymorphic markers can be the ones of the group specified herein or they can be different polymorphic markers that are not specified herein.
  • the method comprises obtaining sequence data about at least two polymorphic markers.
  • each of the markers may be associated with a different gene.
  • the method comprises obtaining nucleic acid data about a human individual identifying at least one allele of a polymorphic marker, then the method comprises identifying at least one allele of at least one polymorphic marker.
  • the method can comprise obtaining sequence data about a human individual identifying alleles of multiple, independent markers, which are not in linkage disequilibrium.
  • Linkage Disequilibrium refers to a non-random assortment of two genetic elements. For example, if a particular genetic element (e.g., an allele of a polymorphic marker, or a haplotype) occurs in a population at a frequency of 0.50 (50%) and another element occurs at a frequency of 0.50 (50%), then the predicted occurrance of a person's having both elements is 0.25 (25%), assuming a random distribution of the elements.
  • a particular genetic element e.g., an allele of a polymorphic marker, or a haplotype
  • Allele or haplotype frequencies can be determined in a population by genotyping individuals in a population and determining the frequency of the occurence of each allele or haplotype in the population. For populations of diploids, e.g., human populations, individuals will typically have two alleles or allelic combinations for each genetic element (e.g. , a marker, haplotype or gene).
  • that is ⁇ 1 indicates that historical recombination may have occurred between two sites (recurrent mutation can also cause
  • the measure r 2 represents the statistical correlation between two sites, and takes the value of 1 if only two haplotypes are present.
  • the r 2 measure is arguably the most relevant measure for association mapping, because there is a simple inverse relationship between r 2 and the sample size required to detect association between susceptibility loci and SNPs. These measures are defined for pairs of sites, but for some applications a determination of how strong LD is across an entire region that contains many polymorphic sites might be desirable (e.g. , testing whether the strength of LD differs significantly among loci or across populations, or whether there is more or less LD in a region than predicted under a particular model). Measuring LD across a region is not straightforward, but one approach is to use the measure r, which was developed in population genetics.
  • a significant r 2 value can be at least 0.1 such as at least 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, or at lesat 0.99.
  • the significant r 2 value can be at least 0.2.
  • linkage disequilibrium as described herein refers to linkage disequilibrium characterized by values of
  • linkage disequilibrium represents a correlation between alleles of distinct markers. It is measured by correlation coefficient or
  • linkage disequilibrium is defined in terms of values for both the r 2 and
  • a significant linkage disequilibrium is defined as r 2 > 0. 1 and
  • Linkage disequilibrium can be determined in a single human population, as defined herein, or it can be determined in a collection of samples comprising individuals from more than one human population. In one embodiment of the invention, LD is determined in a sample from one or more of the HapMap populations (Caucasian, african, japanese,
  • LD is determined in the CEU population of the HapMap samples. In another embodiment, LD is determined in the YRI population. In yet another embodiment, LD is determined in samples from the Icelandic population .
  • surrogate marker tables list markers that are correlated with rs3798220 and rsl0455872 by values of r 2 > 0.2. These tables thus provide exemplary surrogate markers that are useful in the methods and other aspects of the invention as described in more detail herein.
  • Surrogate Marker Table Surrogate markers on Chromosome 6 that are correlated by values of the correlation coefficient r 2 >0.2 to anchor marker rs3798220 (A) and rsl0455872 (B).
  • chr6 159900330 159900330 159980339 0.265102 C T 1 chr6 : 160210523 160210523 160290532 0.281774 T c 2 chr6 : 160357007 160357007 160437016 0.294515 T c 3 chr6 : 160535857 160535857 160615866 0.438387 G A 4 chr6 : 160607402 rsl0080815 160607402 160687411 0.961028 G T 5 chr6 : 160671113 rs9295127 160671113 160751122 0.946698 A c 6 chr6 : 160671521 rs9295128 160671521 160751530 0.501996 T G 7 chr6 : 160679543 rs9457906 160679543 160759552 0.948117 G C 8 chr6 : 160736399 rsl510226 160736399
  • Haplotype blocks can be used to map associations between phenotype and haplotype status, using single markers or haplotypes comprising a plurality of markers.
  • the main haplotypes can be identified in each haplotype block, and then a set of "tagging" SNPs or markers (the smallest set of SNPs or markers needed to distinguish among the
  • haplotypes can then be identified. These tagging SNPs or markers can then be used in assessment of samples from groups of individuals, in order to identify association between phenotype and haplotype. If desired, neighboring haplotype blocks can be assessed concurrently, as there may also exist linkage disequilibrium among the haplotype blocks. Suitable surrogate markers may be selected using public information, such as from the International HapMap Consortium (http://www.hapmap.org) and the International
  • the markers may also be suitably selected from results of whole-genome sequencing.
  • Markers with values of r 2 equal to 1 are perfect surrogates for the at-risk variants, i.e. genotypes for one marker perfectly predicts genotypes for the other. In other words, the surrogate will, by necessity, give exactly the same association data to any particular disease as the anchor marker. Markers with smaller values of r 2 than 1 can also be surrogates for the at-risk anchor variant.
  • the Fisher exact test can be used to calculate two- sided p-values for each individual allele. Correcting for relatedness among patients can be done by extending a variance adjustment procedure previously described (Risch, N. & Teng, J. Genome Res., 8: 1273-1288 (1998)) for sibships so that it can be applied to general familial relationships.
  • the method of genomic controls (Devlin, B. & Roeder, K. Biometrics 55:997 (1999)) can also be used to adjust for the relatedness of the individuals and possible stratification.
  • relative risk and the population attributable risk (PAR) can be calculated assuming a multiplicative model (haplotype relative risk model) (Terwilliger, J .D. & Ott, J., Hum. Hered. 42: 337-46 (1992) and Falk, C.T. & Rubinstein, P, Ann. Hum. Genet. 51 (Pt 3J: 227-33 (1987)), i.e., that the risks of the two alleles/haplotypes a person carries multiply.
  • RR is the risk of A relative to a
  • the risk of a person homozygote AA will be RR times that of a heterozygote Aa and RR 2 times that of a homozygote aa.
  • the multiplicative model has a nice property that simplifies analysis and computations— haplotypes are independent, i.e., in Hardy-Weinberg
  • haplotype counts of the affecteds and controls each have multinomial distributions, but with different haplotype frequencies under the alternative hypothesis.
  • an individual who is at an increased susceptibility (i.e., increased risk) for a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease is an individual in whom at least one specific allele at one or more polymorphic marker conferring increased susceptibility (increased risk) for the condition is identified.
  • the at-risk marker allele is one that confers an increased risk (increased susceptibility) of the condition.
  • significance associated with a marker is measured by a relative risk (RR).
  • significance associated with a marker is measured by an odds ratio (OR).
  • the significance is measured by a percentage.
  • a significant increased risk is measured as a risk (relative risk and/or odds ratio) of at least 1.05, including but not limited to: at least 1.05, at least 1.06, at least 1.07, at least 1.08, at least 1.09, at least 1.10, at least 1.11, at least 1.12, at least 1.13, at least 1.14, at least 1.15, at least 1.16, at least 1.17, at least 1.18, at least 1.19, at least 1.20, at least 1.30, at least 1.40, at least 1.50, at least 1.60, at least 1.70, at least 1.80, at least 1.90, and at least 2.0.
  • a risk (relative risk and/or odds ratio) of at least 1.05 is significant.
  • a risk of at least 1.10 is significant. In yet another embodiment, a risk of at least 1.13 is significant.
  • Other cutoffs are also contemplated, e.g., at least 1.15, 1.25, 1.35, and so on, and such cutoffs are also within scope of the present invention.
  • a significant increase in risk is at least about 5%, including but not limited to at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, and at least about 80%.
  • a significant increase in risk is characterized by a p-value, such as a p-value of less than 0.05, less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.00000001, or less than 0.000000001.
  • An at-risk polymorphic markers as described herein is one where at least one allele of at least one polymorphic marker is more frequently present in an individual at risk for the condition (affected), or diagnosed with the condition, compared to the frequency of its presence in a comparison group (control), such that the presence of the marker or haplotype is indicative of susceptibility to the condition.
  • the control group may in one embodiment be a population sample, i.e. a random sample from the general population.
  • the control group is represented by a group of individuals who are disease-free, i.e. have not been diagnosed with the condition or are do not have one or more specific disease-associated symptoms.
  • an individual who is at a decreased susceptibility (i.e., at a decreased risk) for the condition is an individual in whom at least one specific marker allele conferring decreased susceptibility for the condition is identified.
  • the marker alleles conferring decreased risk are also said to be protective.
  • the protective marker allele is one that confers a significant decreased risk (or susceptibility) of the condition.
  • significant decreased risk is measured as a relative risk (or odds ratio) of less than 0.95, including but not limited to less than 0.9, less than 0.85, less than 0.8, less than 0.75, and less than 0.7.
  • significant decreased risk is less than 0.9.
  • significant decreased risk is less than 0.85.
  • the decrease in risk is at least 5%, including but not limited to at least 10% at least 13%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, and at least 50%.
  • a significant decrease in risk is at least about 5%.
  • a significant decrease in risk is at least about 10%.
  • the decrease in risk is at least about 15%.
  • Other cutoffs or ranges as deemed suitable by the person skilled in the art to characterize the invention are however also contemplated, and those are also within scope of the present invention.
  • markers with two alleles present in the population being studied such as SNPs
  • one allele is found in increased frequency in a group of individuals with a condition such as large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease
  • the other allele of the marker will be found in decreased frequency in the group of individuals with the condition, compared with controls.
  • one allele of the marker (the one found in increased frequency in individuals with the condition) will be the at-risk allele, while the other allele will be a protective allele.
  • a genetic variant associated with a disease or condition can be used alone to predict the risk of the disease or condition for a given genotype.
  • a biallelic marker such as a SNP
  • Risk associated with variants at multiple loci can be used to estimate overall risk.
  • there are k possible genotypes k 3 n x 2"; where n is the number autosomal loci and p the number of gonosomal (sex chromosomal) loci.
  • Overall risk assessment calculations for a plurality of risk variants usually assume that the relative risks of different genetic variants multiply, i.e.
  • the overall risk (e.g., RR or OR) associated with a particular genotype combination is the product of the risk values for the genotype at each locus. If the risk presented is the relative risk for a person, or a specific genotype for a person, compared to a reference population with matched gender and ethnicity, then the combined risk - is the product of the locus specific risk values - and which also corresponds to an overall risk estimate compared with the population. If the risk for a person is based on a comparison to non-carriers of the at risk allele, then the combined risk corresponds to an estimate that compares the person with a given combination of genotypes at all loci to a group of individuals who do not carry risk variants at any of those loci. The group of non- carriers of any at risk variant has the lowest estimated risk and has a combined risk
  • non-carriers compared with itself ⁇ i.e. , non-carriers) of 1.0, but has an overall risk, compare with the population, of less than 1.0. It should be noted that the group of non-carriers can potentially be very small, especially for large number of loci, and in that case, its relevance is
  • multiplicative model is a parsimonious model that usually fits the data of complex traits reasonably well. Deviations from multiplicity have been rarely described in the context of common variants for common diseases, and if reported are usually only suggestive since very large sample sizes are usually required to be able to demonstrate statistical interactions between loci.
  • an absolute risk of developing a disease or trait defined as the chance of a person developing the specific disease or trait over a specified time-period.
  • a woman's lifetime absolute risk of breast cancer is one in nine. That is to say, one woman in every nine will develop breast cancer at some point in their lives.
  • Risk is typically measured by looking at very large numbers of people, rather than at a particular individual. Risk is often presented in terms of Absolute Risk (AR) and Relative Risk (RR).
  • AR Absolute Risk
  • RR Relative Risk
  • Relative Risk is used to compare risks associating with two variants or the risks of two different groups of people. For example, it can be used to compare a group of people with a certain genotype with another group having a different genotype.
  • a relative risk of 2 means that one group has twice the chance of developing a disease as the other group.
  • the creation of a model to calculate the overall genetic risk involves two steps: i) conversion of odds-ratios for a single genetic variant into relative risk and ii) combination of risk from multiple variants in different genetic loci into a single relative risk value.
  • allelic odds-ratio equals the risk factor:
  • the risk relative to the average population risk It is most convenient to represent the risk of a genetic variant relative to the average population since it makes it easier to communicate the lifetime risk for developing the disease compared with the baseline population risk. For example, in the multiplicative model we can calculate the relative population risk for variant "aa" as:
  • RR(aa) Pr(A
  • aa)/Pr(A) (Pr(A
  • bb)) r 2 /(Pr(aa) r 2 +
  • p and "q” are the allele frequencies of "a” and "b” respectively.
  • the allele frequency estimates may be obtained from the publications that report the odds-ratios and from the HapMap database. Note that in the case where we do not know the genotypes of an individual, the relative genetic risk for that test or marker is simply equal to one.
  • RR(gl,g2) RR(gl)RR(g2)
  • g l,g2) Pr(A
  • g2)/Pr(A) and Pr(g l,g2) Pr(g l)Pr(g2)
  • the model applied is not expected to be exactly true since it is not based on an underlying bio-physical model.
  • the multiplicative model has so far been found to fit the data adequately, i.e. no significant deviations are detected for many common diseases for which many risk variants have been discovered.
  • the lifetime risk of an individual is derived by multiplying the overall genetic risk relative to the population with the average life-time risk of the disease in the general population of the same ethnicity and gender and in the region of the individual's geographical origin. As there are usually several epidemiologic studies to choose from when defining the general population risk, we will pick studies that are well-powered for the disease definition that has been used for the genetic variants.
  • the methods and kits of the invention can be utilized from samples containing nucleic acid material (DNA or RNA) from any source and from any individual, or from genotype data derived from such samples.
  • the individual is a human individual.
  • the individual can be an adult, child, or fetus.
  • the nucleic acid source may be any sample comprising nucleic acid material, including biological samples, or a sample comprising nucleic acid material derived therefrom.
  • the present invention also provides for assessing markers and/or haplotypes in individuals who are members of a target population.
  • Such a target population is in one embodiment a population or group of individuals at risk of developing the disease, based on other genetic factors, biomarkers ⁇ e.g., leukotrienes), biophysical parameters, or general health and/or lifestyle parameters (e.g., history of a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease).
  • biomarkers e.g., leukotrienes
  • biophysical parameters e.g., history of a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease.
  • the invention provides for embodiments that include individuals from specific age subgroups, such as those over the age of 40, over age of 45, or over age of 50, 55, 60, 65, 70, 75, 80, or 85.
  • Other embodiments of the invention pertain to other age groups, such as individuals aged less than 85, such as less than age 80, less than age 75, or less than age 70, 65, 60, 55, 50, 45, 40, 35, or age 30.
  • Other embodiments relate to individuals with age at onset of a condition such as large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, coronary artery disease and severe coronary artery disease in any of the age ranges described in the above.
  • the polymorphic markers of the invention are predictive of increased susceptibility to coronary arter disease in individuals with onset of the disease before age 50 for males and before age 60 for females. It is also contemplated that a range of ages may be relevant in certain embodiments, such as age at onset at more than age 45 but less than age 60. Other age ranges are however also contemplated, including all age ranges bracketed by the age values listed in the above.
  • the invention furthermore relates to individuals of either gender, males or females.
  • the Icelandic population is a Caucasian population of Northern European ancestry.
  • a large number of studies reporting results of genetic linkage and association in the Icelandic population have been published in the last few years. Many of those studies show replication of variants, originally identified in the Icelandic population as being associating with a particular disease, in other populations (Styrkarsdottir, U., et a/. N Engl J Med Apr 29 2008 (Epub ahead of print); Thorgeirsson, T., et a/. Nature 452: 638-42 (2008); Gudmundsson, J., et al. Nat Genet. 40: 281-3 (2008); Stacey, S. N., et al., Nat Genet. 39: 865-69 (2007);
  • Such embodiments relate to human subjects that are from one or more human population including, but not limited to, Caucasian populations, European populations, American populations, Eurasian populations, Asian populations, Central/South Asian populations, East Asian populations, Middle Eastern populations, African populations, Hispanic populations, and Oceanian populations.
  • European populations include, but are not limited to, Swedish, Norwegian, Finnish, Russian, Danish, Icelandic, Irish, Kelt, English, Scottish, Dutch, Belgian, French, German, Spanish, Portuguese, Italian, Polish, Bulgarian, Slavic, Serbian, Laun, Czech, Greek and Turkish populations.
  • the invention relates to markers and/or haplotypes identified in specific populations, as described in the above.
  • measures of linkage disequilibrium (LD) may give different results when applied to different populations. This is due to different population history of different human populations as well as differential selective pressures that may have led to differences in LD in specific genomic regions.
  • certain markers e.g. SNP markers, have different population frequency in different populations, or are polymorphic in one population but not in another. The person skilled in the art will however apply the methods available and as thought herein to practice the present invention in any given human population.
  • This may include assessment of polymorphic markers in the LD region of the present invention, so as to identify those markers that give strongest association within the specific population.
  • the at-risk variants of the present invention may reside on different haplotype background and in different frequencies in various human populations.
  • the invention can be practiced in any given human population.
  • Polymorphic markers associated with increased susceptibility of a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early- onset coronary artery disease and severe coronary artery disease are useful in diagnostic methods. While methods of diagnosing cardiovascular diseases are known in the art, the detection risk markers for the condition advantageously may be useful for detection of these condition at their early stages and may also reduce the occurrence of misdiagnosis.
  • the invention further provides methods of diagnosing a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease, comprising obtaining sequence data identifying at least one risk allele as described herein, in conjunction with carrying out one or more clinical diagnostic steps for the identification of the condition.
  • the clinical diagnostics steps may include any such steps known to the skilled person and routinely used in the art.
  • a sample containing genomic DNA or protein from an individual is collected.
  • sample can for example be a buccal swab, a saliva sample, a blood sample, or other suitable samples containing genomic DNA or protein, as described further herein.
  • the sample is obtained by non-invasive means (e.g., for obtaining a buccal sample, saliva sample, hair sample or skin sample).
  • non-surgical means i.e. in the absence of a surgical intervention on the individual that puts the individual at substantial health risk.
  • Such embodiments may, in addition to non-invasive means also include obtaining sample by extracting a blood sample (e.g., a venous blood sample).
  • genomic DNA or protein obtained from the individual is then analyzed using any common technique available to the skilled person, such as high- throughput technologies for genotyping and/or sequencing. Results from such methods are stored in a convenient data storage unit, such as a data carrier, including computer databases, data storage disks, or by other convenient data storage means.
  • the computer database is an object database, a relational database or a post- relational database.
  • the genotype data is subsequently analyzed for the presence of certain variants known to be susceptibility variants for a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease.
  • Genotype and/or sequencing data can be retrieved from the data storage unit using any convenient data query method.
  • Calculating risk conferred by a particular genotype for the individual can be based on comparing the genotype of the individual to previously determined risk (expressed as a relative risk (RR) or and odds ratio (OR), for example) for the genotype, for example for an heterozygous carrier of an at-risk variant.
  • the calculated risk for the individual can be the relative risk for a person, or for a specific genotype of a person, compared to the average population with matched gender and ethnicity.
  • the average population risk can be expressed as a weighted average of the risks of different genotypes, using results from a reference population, and the appropriate calculations to calculate the risk of a genotype group relative to the population can then be performed.
  • the risk for an individual is based on a comparison of particular genotypes, for example heterozygous carriers of an at-risk allele of a marker compared with non-carriers of the at-risk allele.
  • the calculated risk estimated can be made available to the customer via a website, preferably a secure website.
  • Kits useful in the methods of the invention comprise components useful in any of the methods described herein, including for example, primers for nucleic acid amplification, hybridization probes, restriction enzymes (e.g., for RFLP analysis), allele-specific oligonucleotides, antibodies that bind to an altered polypeptide encoded by a nucleic acid of the invention as described herein (e.g., a genomic segment comprising at least one polymorphic marker of the present invention) or to a non-altered (native) polypeptide encoded by a nucleic acid of the invention as described herein, means for amplification of a nucleic acid associated with a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease, means for analyzing the nucleic acid sequence of a nucleic acid associated with the condition, means for analyzing the amino acid sequence of a polypeptide encoded by a nucleic acid
  • kits can for example include necessary buffers, nucleic acid primers for amplifying nucleic acids of the invention (e.g., a nucleic acid segment comprising one or more of the polymorphic markers as described herein), and reagents for allele-specific detection of the fragments amplified using such primers and necessary enzymes (e.g., dna polymerase). Additionally, kits can provide reagents for assays to be used in combination with the methods of the present invention, e.g., reagents for use with other diagnostic assays for the condition.
  • nucleic acid primers for amplifying nucleic acids of the invention e.g., a nucleic acid segment comprising one or more of the polymorphic markers as described herein
  • reagents for allele-specific detection of the fragments amplified using such primers and necessary enzymes e.g., dna polymerase.
  • kits can provide reagents for assays to be used in combination with the methods of the
  • the invention pertains to a kit for assaying a sample from a subject to detect a susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a subject, wherein the kit comprises reagents necessary for selectively detecting at least one allele of at least one polymorphism of the present invention in the genome of the individual.
  • the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising at least one polymorphism of the present invention.
  • the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic segment obtained from a subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes at least one polymorphism associated with risk of the condition.
  • the polymorphism is selected from the group consisting of the markers described herein, and polymorphic markers in linkage disequilibrium therewith.
  • the fragment is at least 20 base pairs in size.
  • kits can be designed using portions of the nucleic acid sequence flanking polymorphisms (e.g., SNPs or microsatellites) that are associated with risk of the condition.
  • the kit comprises one or more labeled nucleic acids capable of allele- specific detection of one or more specific polymorphic markers or haplotypes, and reagents for detection of the label.
  • Suitable labels include, e.g., a radioisotope, a fluorescent label, an enzyme label, an enzyme co-factor label, a magnetic label, a spin label, an epitope label.
  • the polymorphic marker to be detected by the reagents of the kit comprises at least the marker rs3798220 and/or rsl0455872.
  • the reagents of the kit may also be suitable for detecting a marker in linkage disequilibrium with rs3798220 and/or rsl0455872.
  • the marker to be detected comprises at least one marker from the group of markers in strong linkage disequilibrium, as defined by values of r 2 greater than 0.2, to marker rs3798220 and/or rsl0455872.
  • the marker to be detected comprises at least one marker from the group of markers in strong linkage disequilibrium, as defined by values of r 2 greater than 0.5, to marker rs3798220 and/or rsl0455872.
  • the DNA template containing the SIMP polymorphism is amplified by Polymerase Chain Reaction (PCR) prior to detection, and primers for such amplification are included in the reagent kit.
  • PCR Polymerase Chain Reaction
  • the amplified DNA serves as the template for the detection probe and the enhancer probe.
  • determination of the presence of a particular marker allele using the reagents of the kit is indicative of a susceptibility (increased susceptibility or decreased susceptibility) to the condition.
  • determination of the presence of a marker allele is indicative of response to a therapeutic agent for the condition.
  • the presence of the marker allele is indicative of prognosis of the condition.
  • the presence of the marker allele is indicative of progress of treatment of the condition. Such treatment may include intervention by surgery, medication or by other means (e.g., lifestyle changes).
  • a pharmaceutical pack comprising a therapeutic agent and a set of instructions for administration of the therapeutic agent to humans diagnostically tested for one or more variants of the present invention, as disclosed herein.
  • the therapeutic agent can be a small molecule drug, an antibody, a peptide, an antisense or rnai molecule, or other therapeutic molecules.
  • an individual identified as a carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent.
  • an individual identified as a homozygous carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent.
  • an individual identified as a non-carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent.
  • the kit further comprises a set of instructions for using the reagents comprising the kit.
  • the kit further comprises a collection of data comprising correlation data between the polymorphic markers assessed by the kit and susceptibility to the condition.
  • nucleic acids and/or variants described herein, or nucleic acids comprising their complementary sequence may be used as antisense constructs to control gene expression in cells, tissues or organs.
  • the methodology associated with antisense techniques is well known to the skilled artisan, and is for example described and reviewed in AntisenseDrug
  • antisense agents are comprised of single stranded oligonucleotides (RNA or DNA) that are capable of binding to a complimentary nucleotide segment. By binding the appropriate target sequence, an RNA-RNA, DNA-DNA or RNA-DNA duplex is formed.
  • the antisense oligonucleotides are complementary to the sense or coding strand of a gene. It is also possible to form a triple helix, where the antisense oligonucleotide binds to duplex DNA.
  • antisense oligonucleotide Several classes of antisense oligonucleotide are known to those skilled in the art, including cleavers and blockers.
  • the former bind to target RNA sites, activate intracellular nucleases ⁇ e.g., RnaseH or Rnase L), that cleave the target RNA.
  • Blockers bind to target RNA, inhibit protein translation by steric hindrance of the ribosomes. Examples of blockers include nucleic acids, morpholino compounds, locked nucleic acids and methylphosphonates (Thompson, Drug Discovery Today, 7:912-917 (2002)).
  • Antisense oligonucleotides are useful directly as therapeutic agents, and are also useful for determining and validating gene function, for example by gene knock-out or gene knock-down experiments. Antisense technology is further described in Lavery et a/., Curr. Opin. Drug Discov. Devel. 6: 561-569 (2003), Stephens et al., Curr. Opin. Mol. Ther. 5: 118-122 (2003), Kurreck, Eur. J. Biochem.
  • Antisense nucleotides can be from 5-500 nucleotides in length, including 5-200 nucleotides, 5-100 nucleotides, 10-50 nucleotides, and 10-30 nucleotides. In certain preferred embodiments, the antisense nucleotides is from 14-50 nucleotides in length, includign 14-40 nucleotides and 14-30 nucleotides. In certain such embodiments, the antisense nucleotide is capable of binding to a nucleotide segment with sequence as set forth in any one of SEQ ID N0: l-114.
  • the variants described herein can also be used for the selection and design of antisense reagents that are specific for particular variants. Using information about the variants described herein, antisense oligonucleotides or other antisense molecules that specifically target mRNA molecules that contain one or more variants of the invention can be designed. In this manner, expression of mRNA molecules that contain one or more variant of the present invention (markers and/or haplotypes) can be inhibited or blocked.
  • the antisense molecules are designed to specifically bind a particular allelic form (i.e., one or several variants (alleles and/or haplotypes)) of the target nucleic acid, thereby inhibiting translation of a product originating from this specific allele or haplotype, but which do not bind other or alternate variants at the specific polymorphic sites of the target nucleic acid molecule.
  • allelic form i.e., one or several variants (alleles and/or haplotypes)
  • the molecules can be used for disease treatment.
  • the methodology can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated.
  • Such mRNA regions include, for example, protein-coding regions, in particular protein-coding regions corresponding to catalytic activity, substrate and/or ligand binding sites, or other functional domains of a protein.
  • RNAi Clinical applications of RNAi include the incorporation of synthetic siRNA duplexes, which preferably are approximately 20-23 nucleotides in size, and preferably have 3' overlaps of 2 nucleotides. Knockdown of gene expression is established by sequence-specific design for the target mRNA. Several commercial sites for optimal design and synthesis of such molecules are known to those skilled in the art.
  • siRNA molecules typically 25-30 nucleotides in length, preferably about 27 nucleotides
  • shRNAs small hairpin RNAs
  • the latter are naturally expressed, as described in Amarzguioui et a/. ⁇ FEBS Lett. 579: 5974-81 (2005)).
  • Chemically synthetic siRNAs and shRNAs are substrates for in vivo processing, and in some cases provide more potent gene-silencing than shorter designs (Kim et al., Nature Biotechnol. 23: 222-226 (2005); Siolas et al., Nature Biotechnol. 23: 227-231 (2005)).
  • siRNAs provide for transient silencing of gene expression, because their intracellular concentration is diluted by subsequent cell divisions.
  • expressed shRNAs mediate long-term, stable knockdown of target transcripts, for as long as transcription of the shRNA takes place (Marques et al., Nature Biotechnol. 23: 559-565 (2006); Brummelkamp et al., Science 296: 550-553 (2002)).
  • RNAi molecules including siRNA, miRNA and shRNA
  • the variants presented herein can be used to design RNAi reagents that recognize specific nucleic acid molecules comprising specific alleles and/or haplotypes ⁇ e.g., the alleles and/or haplotypes of the present invention), while not recognizing nucleic acid molecules comprising other alleles or haplotypes.
  • RNAi reagents can thus recognize and destroy the target nucleic acid molecules.
  • RNAi reagents can be useful as therapeutic agents (i.e., for turning off disease-associated genes or disease-associated gene variants), but may also be useful for characterizing and validating gene function ⁇ e.g., by gene knock-out or gene knock-down experiments).
  • RNAi may be performed by a range of methodologies known to those skilled in the art. Methods utilizing non-viral delivery include cholesterol, stable nucleic acid-lipid particle (SNALP), heavy-chain antibody fragment (Fab), aptamers and nanoparticles. Viral delivery methods include use of lentivirus, adenovirus and adeno-associated virus.
  • the siRNA molecules are in some embodiments chemically modified to increase their stability. This can include modifications at the 2' position of the ribose, including 2'-0-methylpurines and 2'- fluoropyrimidines, which provide resistance to Rnase activity. Other chemical modifications are possible and known to those skilled in the art.
  • the variants of the present invention may determine the manner in which a therapeutic agent and/or therapeutic method acts on the body, or the way in which the body metabolizes the therapeutic agent.
  • the presence of a particular at-risk allele for a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease is indicative of a different response, e.g. a different response rate, to a particular treatment modality for the condition.
  • a patient diagnosed with the condition, and carrying a certain allele at a polymorphic of the present invention e.g. , the at-risk alleles allele C in rs3798220 and/or allele G in rsl0455872 would respond better to, or worse to, a specific therapeutic, drug and/or other therapy used to treat the condition.
  • the presence or absence of the marker allele could aid in deciding what treatment should be used for the patient.
  • the presence of a marker of the present invention may be assessed (e.g. , through testing DNA derived from a blood sample, as described herein). If the patient is positive for a marker allele, then the physician recommends one particular therapy, while if the patient is negative for the at least one allele of a marker, or a haplotype, then a different course of therapy may be recommended (which may include recommending that no immediate therapy, other than serial monitoring for progression of the condition, be performed). Thus, the patient's carrier status could be used to help determine whether a particular treatment modality should be administered.
  • the value lies within the possibilities of being able to diagnose the disease at an early stage, to select the most appropriate treatment, and provide information to the clinician about prognosis/aggressiveness of the disease in order to be able to apply the most appropriate treatment.
  • the treatment modality may be any suitable treatment modality used for treating the condition. In certain embodiments, the treatment modality is surgical intervention.
  • the present invention also relates to methods of monitoring progress or effectiveness of a treatment for a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease.
  • This can be done based on the genotype status (i.e., the presence or absence of particular alleles) of an individual for the at-risk alleles for the condition described herein, i.e., by assessing the absence or presence of at least one allele of at least one polymorphic marker as disclosed herein.
  • the genotype status of at least one risk variant for the condition as presented herein is determined before and during treatment to monitor its effectiveness.
  • the markers and haplotypes of the present invention can be used for targeting the selection of pharmaceutical agents for specific individuals.
  • Personalized selection of treatment modalities, lifestyle changes or combination of lifestyle changes and administration of particular treatment can be realized by the utilization of the at-risk variants of the present invention.
  • the knowledge of an individual's status for particular risk alleles for a cardiovascular condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease, as described herein, can be useful for selection of appropriate treatment options.
  • nucleic acids and polypeptides described herein can be used in methods and kits of the present invention.
  • An "isolated" nucleic acid molecule is one that is separated from nucleic acids that normally flank the gene or nucleotide sequence (as in genomic sequences) and/or has been completely or partially purified from other transcribed sequences (e.g., as in an RNA library).
  • an isolated nucleic acid of the invention can be substantially isolated with respect to the complex cellular milieu in which it naturally occurs, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized.
  • the isolated material will form part of a composition (for example, a crude extract containing other substances), buffer system or reagent mix.
  • the material can be purified to essential homogeneity, for example as determined by polyacrylamide gel electrophoresis (PAGE) or column chromatography (e.g., HPLC).
  • An isolated nucleic acid molecule of the invention can comprise at least about 50%, at least about 80% or at least about 90% (on a molar basis) of all macromolecular species present.
  • genomic DNA the term "isolated" also can refer to nucleic acid molecules that are separated from the chromosome with which the genomic DNA is naturally associated.
  • the isolated nucleic acid molecule can contain less than about 250 kb, 200 kb, 150 kb, 100 kb, 75 kb, 50 kb, 25 kb, 10 kb, 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of the nucleotides that flank the nucleic acid molecule in the genomic DNA of the cell from which the nucleic acid molecule is derived.
  • nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated.
  • recombinant DNA contained in a vector is included in the definition of "isolated” as used herein.
  • isolated nucleic acid molecules include recombinant DNA molecules in heterologous host cells or heterologous organisms, as well as partially or substantially purified DNA molecules in solution.
  • isolated nucleic acid molecules also encompass in vivo and in vitro RNA transcripts of the DNA molecules of the present invention.
  • An isolated nucleic acid molecule or nucleotide sequence can include a nucleic acid molecule or nucleotide sequence that is synthesized chemically or by recombinant means.
  • Such isolated nucleotide sequences are useful, for example, in the manufacture of the encoded polypeptide, as probes for isolating homologous sequences (e.g. , from other mammalian species), for gene mapping (e.g. , by in situ hybridization with chromosomes), or for detecting expression of the gene in tissue (e.g., human tissue), such as by Northern blot analysis or other hybridization techniques.
  • homologous sequences e.g. , from other mammalian species
  • gene mapping e.g. , by in situ hybridization with chromosomes
  • tissue e.g., human tissue
  • the invention also pertains to nucleic acid molecules that hybridize under high stringency hybridization conditions, such as for selective hybridization, to a nucleotide sequence described herein (e.g., nucleic acid molecules that specifically hybridize to a nucleotide sequence containing a polymorphic site associated with a marker or haplotype described herein).
  • nucleic acid molecules can be detected and/or isolated by allele- or sequence- specific hybridization (e.g., under high stringency conditions).
  • Stringency conditions and methods for nucleic acid hybridizations are well known to the skilled person (see, e.g., Current Protocols in Molecular Biology, Ausubel, F. et al, John Wiley & Sons, (1998), and
  • the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, of the length of the reference sequence.
  • Another example of an algorithm is BLAT (Kent, W.J . Genome Res. 12 : 656-64 (2002)) .
  • the present invention also provides isolated nucleic acid molecules that contain a fragment or portion that hybridizes under highly stringent conditions to a nucleic acid that comprises, or consists of, the nucleotide sequence of at least one polymorphic allele contained in the markers and haplotypes described herein.
  • the nucleic acid fragments of the invention are at least about 15, at least about 18, 20, 23 or 25 nucleotides, and can be 30, 40, 50, 100, 200, 500, 1000, 10,000 or more nucleotides in length. In certain embodiments, the nucleic acid fragments are from about 15 to about 1000 nucleotides in length.
  • the nucleic acid fragments are from about 18 to about 100 nucleotides in length, from about 12 to about 50 nucleotides in length, from about 12 to about 40 nucleotides in length, or from about 12 to about 30 nucleotides in length.
  • the present invention further provides isolated nucleic acid molecules that contain a fragment or portion that hybridizes under highly stringent conditions to a nucleic acid that comprises, or consists of, the nucleotide sequence of any one of SEQ ID NO : 1 - 114, as described herein.
  • the nucleic acid fragments can be from 10-600 nucleotides in length, such as from 10 - 500 nucleotides, 12 - 200 nucleotides, 12 - 100 nucleotides, 12 - 50 nucleotides and 12 - 30 nucleotides in length.
  • the nucleic acid fragments of the invention may be used as probes or primers in assays such as those described herein.
  • Probes or “primers” are oligonucleotides that hybridize in a base-specific manner to a complementary strand of a nucleic acid molecule.
  • probes and primers include polypeptide nucleic acids (PIMA), as described in Nielsen, P. et al. , Science 254: 1497- 1500 ( 1991) .
  • a probe or primer comprises a region of nucleotide sequence that hybridizes to at least about 15, typically about 20-25, and in certain embodiments about 40, 50 or 75, consecutive nucleotides of a nucleic acid molecule.
  • the probe or primer comprises at least one allele of at least one polymorphic marker or at least one haplotype described herein, or the complement thereof.
  • a probe or primer can comprise 100 or fewer nucleotides; for example, in certain embodiments from 6 to 50 nucleotides, or, for example, from 12 to 30 nucleotides.
  • the probe or primer is at least 70% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence.
  • the probe or primer is capable of selectively hybridizing to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence.
  • the probe or primer further comprises a label, e.g. , a radioisotope, a fluorescent label, an enzyme label, an enzyme co-factor label, a magnetic label, a spin label, an epitope label.
  • the nucleic acid molecules of the invention such as those described above, can be identified and isolated using standard molecular biology techniques well known to the skilled person.
  • the amplified DNA can be labeled (e.g., radiolabeled, fluorescently labeled) and used as a probe for screening a cDNA library derived from human cells.
  • the cDNA can be derived from mRNA and contained in a suitable vector. Corresponding clones can be isolated, DNA obtained following in vivo excision, and the cloned insert can be sequenced in either or both orientations by art- recognized methods to identify the correct reading frame encoding a polypeptide of the appropriate molecular weight. Using these or similar methods, the polypeptide and the DNA encoding the polypeptide can be isolated, sequenced and further characterized.
  • the methods and information described herein may be implemented, in all or in part, as computer executable instructions on known computer readable media.
  • the methods described herein may be implemented in hardware.
  • the method may be implemented in software stored in, for example, one or more memories or other computer readable medium and implemented on one or more processors.
  • the processors may be associated with one or more controllers, calculation units and/or other units of a computer system, or implanted in firmware as desired.
  • the routines may be stored in any computer readable memory such as in RAM, ROM, flash memory, a magnetic disk, a laser disk, or other storage medium, as is also known.
  • this software may be delivered to a computing device via any known delivery method including, for example, over a communication channel such as a telephone line, the Internet, a wireless connection, etc., or via a transportable medium, such as a computer readable disk, flash drive, etc.
  • a communication channel such as a telephone line, the Internet, a wireless connection, etc.
  • a transportable medium such as a computer readable disk, flash drive, etc.
  • the various steps described above may be implemented as various blocks, operations, tools, modules and techniques which, in turn, may be implemented in hardware, firmware, software, or any combination of hardware, firmware, and/or software.
  • some or all of the blocks, operations, techniques, etc. may be implemented in, for example, a custom integrated circuit (IC), an application specific integrated circuit (ASIC), a field programmable logic array (FPGA), a programmable logic array (PLA), etc.
  • the software When implemented in software, the software may be stored in any known computer readable medium such as on a magnetic disk, an optical disk, or other storage medium, in a RAM or ROM or flash memory of a computer, processor, hard disk drive, optical disk drive, tape drive, etc.
  • the software may be delivered to a user or a computing system via any known delivery method including, for example, on a computer readable disk or other transportable computer storage mechanism.
  • another aspect of the invention is a system that is capable of carrying out a part or all of a method of the invention, or carrying out a variation of a method of the invention as described herein in greater detail.
  • Exemplary systems include, as one or more components, computing systems, environments, and/or configurations that may be suitable for use with the methods and include, but are not limited to, personal computers, server computers, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronics, network PCs, minicomputers, mainframe computers, distributed computing environments that include any of the above systems or devices, and the like.
  • a system of the invention includes one or more machines used for analysis of biological material (e.g., genetic material), as described herein. In some variations, this analysis of the biological material involves a chemical analysis and/or a nucleic acid amplification.
  • an exemplary system of the invention which may be used to implement one or more steps of methods of the invention, includes a computing device in the form of a computer 110.
  • Components shown in dashed outline are not technically part of the computer 110, but are used to illustrate the exemplary embodiment of Fig. 1.
  • Components of computer 110 may include, but are not limited to, a processor 120, a system memory 130, a memory/graphics interface 121, also known as a Northbridge chip, and an I/O interface 122, also known as a Southbridge chip.
  • the system memory 130 and a graphics processor 190 may be coupled to the memory/graphics interface 121.
  • a monitor 191 or other graphic output device may be coupled to the graphics processor 190.
  • a series of system busses may couple various system components including a high speed system bus 123 between the processor 120, the memory/graphics interface 121 and the I/O interface 122, a front-side bus 124 between the memory/graphics interface 121 and the system memory 130, and an advanced graphics processing (AGP) bus 125 between the memory/graphics interface 121 and the graphics processor 190.
  • the system bus 123 may be any of several types of bus structures including, by way of example, and not limitation, such architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus and Enhanced ISA (EISA) bus.
  • ISA Industry Standard Architecture
  • MCA Micro Channel Architecture
  • EISA Enhanced ISA
  • the computer 110 typically includes a variety of computer-readable media.
  • Computer- readable media can be any available media that can be accessed by computer 110 and includes both volatile and nonvolatile media, removable and non-removable media.
  • Computer readable media may comprise computer storage media.
  • Computer storage media includes both volatile and nonvolatile, removable and nonremovable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules or other data.
  • Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other physical medium which can be used to store the desired information and which can accessed by computer 110.
  • the system memory 130 includes computer storage media in the form of volatile and/or nonvolatile memory such as read only memory (ROM) 131 and random access memory (RAM) 132.
  • the system ROM 131 may contain permanent system data 143, such as identifying and manufacturing information.
  • a basic input/output system (BIOS) may also be stored in system ROM 131.
  • RAM 132 typically contains data and/or program modules that are immediately accessible to and/or presently being operated on by processor 120.
  • Fig. 1 illustrates operating system 134, application programs 135, other program modules 136, and program data 137.
  • the I/O interface 122 may couple the system bus 123 with a number of other busses 126, 127 and 128 that couple a variety of internal and external devices to the computer 110.
  • a serial peripheral interface (SPI) bus 126 may connect to a basic input/output system (BIOS) memory 133 containing the basic routines that help to transfer information between elements within computer 110, such as during start-up.
  • BIOS basic input/output system
  • a super input/output chip 160 may be used to connect to a number of 'legacy' peripherals, such as floppy disk 152, keyboard/mouse 162, and printer 196, as examples.
  • the super I/O chip 160 may be connected to the I/O interface 122 with a bus 127, such as a low pin count (LPC) bus, in some embodiments.
  • a bus 127 such as a low pin count (LPC) bus, in some embodiments.
  • LPC low pin count
  • Various embodiments of the super I/O chip 160 are widely available in the commercial marketplace.
  • bus 128 may be a Peripheral Component Interconnect (PCI) bus, or a variation thereof, may be used to connect higher speed peripherals to the I/O interface 122.
  • PCI Peripheral Component Interconnect
  • a PCI bus may also be known as a Mezzanine bus.
  • Variations of the PCI bus include the Peripheral Component Interconnect-Express (PCI-E) and the Peripheral Component
  • bus 128 may be an advanced technology attachment (ATA) bus, in the form of a serial ATA bus (SATA) or parallel ATA (PATA).
  • ATA advanced technology attachment
  • SATA serial ATA bus
  • PATA parallel ATA
  • the computer 110 may also include other removable/non-removable, volatile/nonvolatile computer storage media.
  • Fig. 1 illustrates a hard disk drive 140 that reads from or writes to non-removable, nonvolatile magnetic media.
  • the hard disk drive 140 may be a conventional hard disk drive.
  • Removable media such as a universal serial bus (USB) memory 153, firewire (IEEE 1394), or CD/DVD drive 156 may be connected to the PCI bus 128 directly or through an interface 150.
  • a storage media 154 may be coupled through interface 150.
  • Other removable/nonremovable, volatile/nonvolatile computer storage media that can be used in the exemplary operating environment include, but are not limited to, magnetic tape cassettes, flash memory cards, digital versatile disks, digital video tape, solid state RAM, solid state ROM, and the like.
  • the drives and their associated computer storage media discussed above and illustrated in Fig. 1, provide storage of computer readable instructions, data structures, program modules and other data for the computer 110.
  • hard disk drive 140 is illustrated as storing operating system 144, application programs 145, other program modules 146, and program data 147. Note that these components can either be the same as or different from operating system 134, application programs 135, other program modules 136, and program data 137. Operating system 144, application programs 145, other program modules 146, and program data 147 are given different numbers here to illustrate that, at a minimum, they are different copies.
  • a user may enter commands and information into the computer 20 through input devices such as a mouse/keyboard 162 or other input device combination.
  • Other input devices may include a microphone, joystick, game pad, satellite dish, scanner, or the like. These and other input devices are often connected to the processor 120 through one of the I/O interface busses, such as the SPI 126, the LPC 127, or the PCI 128, but other busses may be used. In some embodiments, other devices may be coupled to parallel ports, infrared interfaces, game ports, and the like (not depicted), via the super I/O chip 160.
  • the computer 110 may operate in a networked environment using logical connections to one or more remote computers, such as a remote computer 180 via a network interface controller (NIC) 170.
  • the remote computer 180 may be a personal computer, a server, a router, a network PC, a peer device or other common network node, and typically includes many or all of the elements described above relative to the computer 110.
  • the logical connection between the NIC 170 and the remote computer 180 depicted in Fig. 1 may include a local area network (LAN), a wide area network (WAN), or both, but may also include other networks.
  • LAN local area network
  • WAN wide area network
  • Such networking environments are commonplace in offices, enterprise-wide computer networks, intranets, and the Internet.
  • the remote computer 180 may also represent a web server supporting interactive sessions with the computer 110, or in the specific case of location-based applications may be a location server or an application server.
  • the network interface may use a modem (not depicted) when a broadband connection is not available or is not used. It will be appreciated that the network connection shown is exemplary and other means of establishing a communications link between the computers may be used.
  • the invention is a system for identifying susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a human subject.
  • the system includes tools for performing at least one step, preferably two or more steps, and in some aspects all steps of a method of the invention, where the tools are operably linked to each other.
  • Operable linkage describes a linkage through which components can function with each other to perform their purpose.
  • a system of the invention is a system for identifying susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a human subject, and comprises:
  • a susceptibility database operatively coupled to a computer-readable medium of the system and containing population information correlating the presence or absence of one or more alleles of at least one polymorphic marker selected from the group consisting of allele C in rs3798220 and allele G in rsl0455872, and marker alleles in linkage disequilibirium therewith susceptibility to the condition in a population of humans;
  • (iii) is adapted to be executed on a processor of the system, to compare the information about the human subject with the population information in the susceptibility database and generate a conclusion with respect to susceptibility to the condition for the human subject.
  • Exemplary processors include all variety of microprocessors and other processing units used in computing devices.
  • Exemplary computer-readable media are described above.
  • the system generally can be created where a single processor and/or computer readable medium is dedicated to a single component of the system; or where two or more functions share a single processor and/or share a single computer readable medium, such that the system contains as few as one processor and/or one computer readable medium.
  • some components of a system may be located at a testing laboratory dedicated to laboratory or data analysis, whereas other components, including components (optional) for supplying input information or obtaining an output communication, may be located at a medical treatment or counseling facility (e.g., doctor's office, health clinic, HMO, pharmacist, geneticist, hospital) and/or at the home or business of the human subject (patient) for whom the testing service is performed.
  • a medical treatment or counseling facility e.g., doctor's office, health clinic, HMO, pharmacist, geneticist, hospital
  • an exemplary system includes a susceptibility database 208 that is operatively coupled to a computer-readable medium of the system and that contains population information correlating the presence or absence of at least one allele of at least one polymorphic marker selected from the group consisting of rs3798220 and marker rsl0455872, and correlated markers in linkage disequilibrium therewith and susceptibility to a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease in a population of humans.
  • the susceptibility database contains 208 data relating to the frequency that a particular allele of the at least one marker has been observed in a population of humans with the condition and a population of humans free of the condition. Such data provides an indication as to the relative risk or odds ratio of developing the condition for a human subject that is identified as having the allele in question.
  • the susceptibility database includes similar data with respect to two or more alleles of at least one marker, thereby providing a useful reference if the human subject has any of the two or more alleles.
  • the susceptibility database includes additional quantitative personal, medical, or genetic information about the individuals in the database diagnosed with the condition or free of the condition.
  • Such information includes, but is not limited to, information about parameters such as age, sex, ethnicity, race, medical history, weight, diabetes status, blood pressure, blood lipids, family history of the condition, smoking history, and alcohol use in humans and impact of the at least one parameter on susceptibility to the condition.
  • the information also can include information about other genetic risk factors for the condition besides these aforementioned markers.
  • the system further includes a measurement tool 206 programmed to receive an input 204 from or about the human subject and generate an output that contains information about the presence or absence of the at least one allele of interest.
  • the input 204 is not part of the system per se but is illustrated in the schematic Figure 2.
  • the input 204 will contain a specimen or contain data from which the presence or absence of the at least one allele can be directly read, or analytically determined.
  • the input contains annotated information about genotypes or allele counts for the markers predictive of risk of the condition in the genome of the human subject, in which case no further processing by the measurement tool 206 is required, except possibly transformation of the relevant information about the presence/absence of the at least one allele into a format compatible for use by the analysis routine 210 of the system.
  • the input 204 from the human subject contains data that is unannotated or insufficiently annotated with respect to the at least one marker, requiring analysis by the measurement tool 206.
  • the input can be genetic sequence of a chromosomal region or chromosome on which the marker resides, or whole genome sequence information, or unannotated information from a gene chip analysis of a variable loci in the human subject's genome.
  • the measurement tool 206 comprises a tool, preferably stored on a computer-readable medium of the system and adapted to be executed on a processor of the system, to receive a data input about a subject and determine information about the presence or absence of the at least one mutant allele in a human subject from the data.
  • the measurement tool 206 contains instructions, preferably executable on a processor of the system, for analyzing the unannotated input data and determining the presence or absence of the allele of interest in the human subject.
  • the input data is genomic sequence information
  • the measurement tool optionally comprises a sequence analysis tool stored on a computer readable medium of the system and executable by a processor of the system with instructions for determining the presence or absence of the at least one mutant allele from the genomic sequence
  • the input 204 from the human subject comprises a biological sample, such as a fluid (e.g., blood) or tissue sample, that contains genetic material that can be analyzed to determine the presence or absence of the allele of interest.
  • a biological sample such as a fluid (e.g., blood) or tissue sample, that contains genetic material that can be analyzed to determine the presence or absence of the allele of interest.
  • an exemplary measurement tool 206 includes laboratory equipment for processing and analyzing the sample to determine the presence or absence (or identity) of the allele(s) in the human subject.
  • the measurement tool includes: an oligonucleotide microarray (e.g., "gene chip") containing a plurality of oligonucleotide probes attached to a solid support; a detector for measuring interaction between nucleic acid obtained from or amplified from the biological sample and one or more oligonucleotides on the oligonucleotide microarray to generate detection data; and an analysis tool stored on a computer-readable medium of the system and adapted to be executed on a processor of the system, to determine the presence or absence of the at least one allele of interest based on the detection data.
  • an oligonucleotide microarray e.g., "gene chip”
  • a detector for measuring interaction between nucleic acid obtained from or amplified from the biological sample and one or more oligonucleotides on the oligonucleotide microarray to generate detection data
  • an analysis tool stored on a computer-readable medium of the system and adapted to be executed on
  • the measurement tool 206 includes: a nucleotide sequencer (e.g., an automated DNA sequencer) that is capable of determining nucleotide sequence information from nucleic acid obtained from or amplified from the biological sample; and an analysis tool stored on a computer-readable medium of the system and adapted to be executed on a processor of the system, to determine the presence or absence of the at least one mutant allele based on the nucleotide sequence information.
  • a nucleotide sequencer e.g., an automated DNA sequencer
  • an analysis tool stored on a computer-readable medium of the system and adapted to be executed on a processor of the system, to determine the presence or absence of the at least one mutant allele based on the nucleotide sequence information.
  • the measurement tool 206 further includes additional equipment and/or chemical reagents for processing the biological sample to purify and/or amplify nucleic acid of the human subject for further analysis using a sequencer, gene chip, or other analytical equipment.
  • the exemplary system further includes an analysis tool or routine 210 that: is operatively coupled to the susceptibility database 208 and operatively coupled to the measurement tool 206, is stored on a computer-readable medium of the system, is adapted to be executed on a processor of the system to compare the information about the human subject with the population information in the susceptibility database 208 and generate a conclusion with respect to susceptibility to the condition for the human subject.
  • the analysis tool 210 looks at the alleles identified by the measurement tool 206 for the human subject, and compares this information to the susceptibility database 208, to determine a
  • the susceptibility can be based on the single parameter (the identity of one or more alleles of one or more markers predictive of risk of the condition), or can involve a calculation based on other genetic and non-genetic data, as described above, that is collected and included as part of the input 204 from the human subject, and that also is stored in the susceptibility database 208 with respect to a population of other humans.
  • each parameter of interest is weighted to provide a conclusion with respect to susceptibility to the condition.
  • Such a conclusion is expressed in the conclusion in any statistically useful form, for example, as an odds ratio, a relative risk, or a lifetime risk for subject developing the condition.
  • the system as just described further includes a communication tool 212.
  • the communication tool is operatively connected to the analysis routine 210 and comprises a routine stored on a computer-readable medium of the system and adapted to be executed on a processor of the system, to: generate a communication containing the conclusion; and to transmit the communication to the human subject 200 or the medical practitioner 202, and/or enable the subject or medical practitioner to access the communication.
  • the subject and medical practitioner are depicted in the schematic Fig. 2, but are not part of the system per se, though they may be considered users of the system.
  • the communication tool 212 provides an interface for communicating to the subject, or to a medical practitioner for the subject (e.g., doctor, nurse, genetic counselor), the conclusion generated by the analysis tool 210 with respect to susceptibility to the condition for the subject.
  • a medical practitioner for the subject (e.g., doctor, nurse, genetic counselor)
  • the medical practitioner will share the communication with the human subject 200 and/or counsel the human subject about the medical significance of the communication.
  • the communication is provided in a tangible form, such as a printed report or report stored on a computer readable medium such as a flash drive or optical disk.
  • the communication is provided electronically with an output that is visible on a video display or audio output (e.g., speaker).
  • the communication is transmitted to the subject or the medical practitioner, e.g., electronically or through the mail.
  • the system is designed to permit the subject or medical practitioner to access the communication, e.g., by telephone or computer.
  • the system may include software residing on a memory and executed by a processor of a computer used by the human subject or the medical practitioner, with which the subject or practitioner can access the communication, preferably securely, over the internet or other network connection.
  • this computer will be located remotely from other components of the system, e.g., at a location of the human subject's or medical practitioner's choosing.
  • the system as described further includes components that add a treatment or prophylaxis utility to the system. For instance, value is added to a determination of susceptibility to the condition when a medical practitioner can prescribe or administer a standard of care that can reduce susceptibility to the condition; and/or delay onset of the condition; and/or increase the likelihood of detecting the condition at an early stage.
  • Exemplary lifestyle change protocols include loss of weight, increase in exercise, cessation of unhealthy behaviors such as smoking, and change of diet.
  • Exemplary medicinal and surgical intervention protocols include administration of pharmaceutical agents for prophylaxis; and surgery.
  • Exemplary diagnostic protocols include non-invasive and invasive imaging;
  • the system further includes a medical protocol database 214 operatively connected to a computer-readable medium of the system and containing information correlating the presence or absence of the at least one marker allele of interest and medical protocols for human subjects at risk for the condition.
  • medical protocols include any variety of medicines, lifestyle changes, diagnostic tests, increased frequencies of diagnostic tests, and the like that are designed to achieve one of the aforementioned goals.
  • the information correlating a marker allele with protocols could include, for example, information about the success with which the condition or its symptoms is avoided or delayed, or success with which the condition is detected early and treated, if a subject has a marker susceptibility allele and follows a protocol.
  • the system of this embodiment further includes a medical protocol tool or routine 216, operatively connected to the medical protocol database 214 and to the analysis tool or routine 210.
  • the medical protocol tool or routine 216 preferably is stored on a computer- readable medium of the system, and adapted to be executed on a processor of the system, to: (i) compare (or correlate) the conclusion that is obtained from the analysis routine 210 (with respect to susceptibility to the condition for the subject) and the medical protocol database 214, and (ii) generate a protocol report with respect to the probability that one or more medical protocols in the medical protocol database will achieve one or more of the goals of reducing susceptibility to the condition; delaying onset of the condition; and increasing the likelihood of detecting the condition at an early stage to facilitate early treatment.
  • the probability can be based on empirical evidence collected from a population of humans and expressed either in absolute terms (e.g., compared to making no intervention), or expressed in relative terms, to highlight the comparative or additive benefits of two or more protocols.
  • Some variations of the system just described include the communication tool 212.
  • the communication tool generates a communication that includes the protocol report in addition to, or instead of, the conclusion with respect to susceptibility.
  • Information about allele status of risk markers of the condition not only can provide useful information about identifying or quantifying susceptibility to the condition; it can also provide useful information about possible causative factors for a human subject identified with the condition, and useful information about therapies for the patient. In some variations, systems of the invention are useful for these purposes.
  • the invention is a system for assessing or selecting a treatment protocol for a subject diagnosed with a condition selected from large artery atherosclerosis, peripheral arterial disease, abdominal aortic aneurysm, early-onset coronary artery disease and severe coronary artery disease.
  • An exemplary system schematically depicted in Figure 3, comprises:
  • a medical treatment database 308 operatively connected to a computer-readable medium of the system and containing information correlating the presence or absence of at least one marker allele selected from the group consisting of allele C in rs3798220 and/or allele G in rsl0455872, and marker alleles correlated therewith, and efficacy of treatment regimens for the condition;
  • a measurement tool 306 to receive an input (304, depicted in Fig. 3 but not part of the system per se) about the human subject and generate information from the input 304 about the presence or absence of the at least one marker allele in a human subject diagnosed with the condition;
  • a medical protocol routine or tool 310 operatively coupled to the medical treatment database 308 and the measurement tool 306, stored on a computer-readable medium of the system, and adapted to be executed on a processor of the system, to compare the information with respect to presence or absence of the at least one marker allele for the subject and the medical treatment database, and generate a conclusion with respect to at least one of:
  • such a system further includes a communication tool 312 operatively connected to the medical protocol tool or routine 310 for communicating the conclusion to the subject 300, or to a medical practitioner for the subject 302 (both depicted in the schematic of Fig. 3, but not part of the system per se).
  • An exemplary communication tool comprises a routine stored on a computer-readable medium of the system and adapted to be executed on a processor of the system, to generate a communication containing the conclusion; and transmit the communication to the subject or the medical practitioner, or enable the subject or medical practitioner to access the communication.
  • the LPA score correlated with Gensini and Duke severity scores in the Atlanta-USA study ( Figure 6) . Effect estimates for African Americans were similar to those of European origin (Table 3 and Figure 6) .
  • LPA variants and the number of coronary arteries (out of 4 index vessels) with > 50% stenosis.
  • Lp(a) levels have an effect on the atherosclerotic burden of large vessels throughout the arterial tree.
  • LPA score did not associate with IMT, a validated marker of subclinical early
  • Lp(a) has been implicated in both atherogenesis and thrombosis.
  • the LPA risk alleles that correlate with increased plasma Lp(a) levels associate with vascular diseases with a strong atherosclerotic component, such as CAD, PAD and LAA, and AAA, but fail to demonstrate an association with diseases without an atherosclerotic aetiology, such as VTE and IA, or with diseases less related to atherosclerosis, such as the CE and SVD stroke subtypes.
  • CAD, PAD and LAA are almost solely due to atherosclerosis.
  • AAA has been considered to be a manifestation of advanced atherosclerosis, as atherosclerosis is very common both in the aneurysmal wall and other circulatory beds of AAA patients 36 ; although it has been debated whether it is causally related to the aneurysms 37 .
  • the ischemic stroke subtypes, CE and SVD are less linked to atherosclerosis as the majority of CE strokes are secondary to atrial fibrillation and the SVD subtype is believed to result from a non-atherothrombotic obstruction of small arteries deep within the brain 38 .
  • VTE is a venous thrombotic disease in which atherosclerosis is not a causative factor although some studies have shown a link between arterial and venous disorders 39 .
  • LAA large artery atherosclerosis
  • CE cardioembolism
  • SVD small vessel disease
  • PAD peripheral arterial disease
  • AAA abdominal aortic aneurysm
  • VTE venous thromboembolism
  • CAD coronary artery disease
  • IA intracranial aneurysm.
  • frq_con a I lei ic frequency in controls
  • frq_case allelic frequency in cases
  • 95% CI 95% confidence interval.
  • LAA large artery atherosclerosis
  • CE cardioembolism
  • SVD small vessel disease
  • PAD peripheral arterial disease
  • AAA abdominal aortic aneurysm
  • VTE venous thromboembolism
  • IA intracranial aneurysm).
  • n e effective sample size (n e case)
  • frq_con a I lei ic frequency in controls
  • frq_case allelic frequency in cases
  • 95% CI 95% confidence interval.
  • CAD Coronary artery disease
  • Late onset diagnosed >70 in men and >75 in women.
  • n e effective sample size (n e case), frq_con :allelic frequency in controls, frq case: allelic frequency in cases, OR:odds ratio, 95% CI: 95% confidence interval.
  • Table 7-A Association of LPA score with LAA, PAD a nd AAA, without concomittant CAD
  • LAA large artery atherosclerosis
  • PAD peripheral arterial disease
  • AAA abdominal aortic aneurysm
  • CAD coronary artery disease
  • n e effective sample size (n e case)
  • frq_con a I lei ic frequency in controls
  • frq_case allelic frequency in cases
  • 95% CI 95% confidence interval.
  • Icela nd (58%) 25617/142 276 0.074 0. .083 1.142 (0.724- 1.802) 0.568
  • New Zealand (26%) 526/117 253 0.082 0. .099 1.231 (0.753-2.013) 0.408
  • USA-CA (48%) 208/190 315 0.087 0. .103 1.207 (0.750- 1.942) 0.438
  • LAA large artery atherosclerosis
  • PAD peripheral arterial disease
  • AAA abdominal aortic aneurysm
  • CAD coronary artery disease
  • frq_con a I lei ic frequency in controls
  • frq_case allelic frequency in cases
  • OR:odds ratio 95% CI: 95% confidence interval.
  • the ischemic stroke or TIA diagnoses were based on standard WHO criteria 43 and imaging evidence (either CT or MRI), and were clinically confirmed by neurologists. Eligible patients who survived the stroke were invited to participate the genetic study, either by attending a recruitment centre for deCODE's genetic studies, or they were visited at their home by a study nurse.
  • Control subjects were participants from a large variety of genetic programs at deCODE.
  • UK- SE The second case control study from the UK, herein referred to as UK- SE included ischemic stroke patients of European descent attending a cerebrovascular service in South East England and were recruited 1995-2002, as previously described 42 . Briefly, all cases were phenotyped by one experienced stroke neurologist with review of original brain imaging with CT or MRI.
  • Germany-W Another German case-control study, referred to as Germany-W, recruited ischemic stroke patients through hospitals participating in the regional Westphalian Stroke Register, during the period 2000-2003, as described elsewhere 42 . Diagnoses were based on clinical findings and imaging evidence (either CT or MRI), and were clinically confirmed by neurologists. Population controls without a self-reported history of stroke were drawn from the prospective, population based Dortmund Health Study.
  • ischemic stroke cases from all studies had ancillary diagnostic investigations including duplex ultrasonography of the carotid and vertebral arteries, echocardiography, Holter monitoring, MRA, CT angiography, and blood tests for prothrombotic state, to provide information about ischemic stroke causative subtypes.
  • Patients were classified into etiologic subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) 46 . Classification was performed independently for stroke populations but in a standardized manner.
  • the TOAST classification 46 includes six categories: (1) large-artery occlusive disease (large vessel disease), (2) cardioembolism (cardiogenic stroke), (3) small vessel disease (lacunar stroke), (4) other determined etiology, (5) etiology unknown despite diagnostic efforts, or (6) more than one etiology.
  • Patients classified into the TOAST categories 4-6 were excluded from the stroke population from Germany-W. In Iceland, patients were classified as having large- artery occlusive disease if stenosis was > 70% which is a stricter criterion than usually used i.e. > 50%.
  • AAA cases were recruited from the Otago-Southland region, the vast majority (>97%) being of Anglo-European ancestry as reported previously 47 . Approximately 80% of cases had undergone surgical AAA repair (typically infrarenal aorta > 50 mm). The control group consisted of elderly individuals with no previous history of vascular disease from the same geographical region. An abdominal ultrasound scan excluded concurrent AAA from the control group and Anglo-European ancestry was required for inclusion. Controls were also asymptomatic for PAD and had ankle brachial indexes > 1. United Kingdom (UK). As previously described 47 , AAA cases included those randomized to surveillance in the UK Small Aneurysm Trial. AAA diameter at baseline was 45 mm (32-55 mm). Controls were of European descent, recruited from England.
  • AAA cases included those admitted for emergency repair of ruptured AAA or for an elective surgery to the University Hospital of Med (Liege, Belgium), or to Dalhousie University Hospital (Halifax, Canada). Controls included spouses of individuals with AAA or subjects admitted to the same hospitals for reasons other than AAA. All cases and controls were of European descent. The Netherlands. As previously described, AAA cases from Utrecht were recruited in 2007-2009 from eight centres in The Netherlands, mainly when individuals visited their vascular surgeon in the polyclinic or, in rare cases, during hospital admission for elective or emergency AAA surgery. An AAA was defined as an infrarenal aorta > 30 mm.
  • Controls included primary care patients that were ascertained through the Geisinger MyCode Project and were frequency matched for age and gender to the Geisinger Vascular Clinic AAA cases. California, USA (USA-CA).
  • the AAA-STOP Abdominal Aortic Aneurysm : Simple Treatment or Prevention
  • the study concentrated on recruiting small aneurysm cases, defined as having a maximal abdominal aortic diameter of >3.0cm and ⁇ 5.0cm by ultrasound at entry. Controls had maximal aortic diameter ⁇ 3.0cm as verified by ultrasound examination. Mean age and range as well as male/female ratio was similar between cases and controls. For the purpose of the current analysis only subjects of European ancestry were used and subjects with CAD were excluded from the control group.
  • PAD cases identified from a registry of individuals diagnosed with PAD during the year 1998-2006, at the Landspitali University Hospital in Reykjavik, were enrolled over a nine year period as part of the CVD genetics program at deCODE 42,47 .
  • the PAD diagnosis was based on vascular imaging or segmental pressure measurements and was clinically confirmed by a vascular surgeon.
  • the Icelandic controls included the same subjects as used for the Icelandic stroke study, described above. New Zealand.
  • PAD cases were recruited from the Otago-Southland region, the vast majority (>97%) being of Anglo-European ancestry as reported previously 47 .
  • PAD diagnosis was confirmed by an ankle brachial index ⁇ 0.7, pulse volume recordings and angiography/ultrasound imaging.
  • Consensus criteria 55 was confirmed by an experienced vascular surgery consultant.
  • the control group consisted of healthy individuals included in a health screening programme for a preventive medicine project. None of those had symptomatic PAD.
  • VTE venous thromboembolism
  • PEDS study Consecutive patients presenting with symptoms or signs suspected by a physician of being caused by acute PE were eligible for the study. Cases with co-morbid condition making life expectancy less than three months, needed long-term use of anticoagulants, were pregnant, or less than 18 years of age, were excluded.
  • Controls For each study, friends of cases were recruited as controls and they were frequency matched to cases by sex, ethnicity, and age. Controls were excluded if they had prior VTE or recent malignant disease.
  • the control group included unrelated individuals without a history of vascular or thromboembolic disease.
  • the controls were randomly selected among blood donors, and traumatology and ophthalmology patients from the same hospitals matched by age, sex, race, and geographic distribution with the cases 58 .
  • the GAIT 1 Genetic Analysis of Idiopathic Thrombophilia study is composed of 21 extended Spanish families recruited in Barcelona. Twelve families were ascertained though a proband with idiopathic thrombophilia, whereas 9 families were randomly selected. Idiopathic thrombophilia was defined as multiple thrombotic events, a single
  • the GAIT 2 study includes an additional set of 15 extended Spanish families recruited in Barcelona. The criteria for inclusion in the study have been described before 59 , and were the same as for the
  • MARTHA MARseille THrombosis Association study
  • cases were consecutively recruited whites with a documented history of VTE and without strong known risk factors, including antithrombin, protein C, or protein S deficiency, homozygosity for FV Leiden or FII 20210A, and lupus anticoagulant, who attended the Thrombophilia Center of La Timone Hospital in France between 1994 and 2005.
  • the thrombotic events were documented by venography, Doppler ultrasound, spiral computed tomographic scanning angiography, and/or ventilation/perfusion lung scan.
  • control group was recruited during the same period and consisted of inpatients and outpatients, frequency matched to cases by age- and sex, and were free of venous and arterial thrombotic disease. Potential controls with cancer, liver or kidney failure, or a history of venous and/or arterial thrombotic disease were excluded.
  • Intracranial aneurysm Intracranial aneurysm
  • IA intracranial aneurysm
  • Diagnosis was based on clinical symptoms, conventional angiography, computed tomography or magnetic resonance angiogram.
  • the controls were healthy Dutch blood bank donors of European origin.
  • IMT Intima media thickness
  • the IMPROVE study includes subjects, (aged 54-79 years), from 7 centers in Italy, Finland, Sweden, the Netherlands and France, who presented at least three vascular risk factors and who had no history of cardiovascular disease or other medical conditions that might limit longevity, were ascertained between 2004-2005 though a longitudinal cohort study. Blood sampling, ultrasound examinations for IMT, and medical history was performed/recorded at baseline and after 30 months. The ultrasonic variable considered for the purpose of the current study was the mean IMT of the common carotid arteries (CCAs) excluding the first centimeter closest to the bifurcation (left and right). The far walls of the left and right CCA were visualized in anterior, lateral and posterior projections and mean IMT measured. IMT measurements were performed in a centralized laboratory using dedicated software.
  • CCAs common carotid arteries
  • CAD Coronary artery disease
  • CAD cases were enrolled as part of the CVD genetics program at deCODE. Cases were identified from a registry of over 10,000 individuals who suffered myocardial infarction (MI) before the age of 75 in Iceland between 1981 and 2002 and satisfied the MONICA criteria 65 . Additional subjects with CAD, were identified from a list of those who have undergone percutaneous coronary intervention (PCI) in the years 1993 to 2003, and from a registry of >23.000 individuals with CAD discharge diagnoses (ICD 9 codes 410.*, 411.*, 412.*, 414.*, or ICD 10 codes 120.0, 121.*, 122.*.
  • PCI percutaneous coronary intervention
  • Coronary angiograms of all subjects were analyzed by an experienced cardiologist, with the extent of CAD expressed as the number of vessel territories out of the 4 index vessels (left main stem, left anterior descending, left circumflex artery, and right coronary artery) with stenoses >50% of the vessel normal reference diameter, using visual assessment of lesion severity 66 . Those with ⁇ 50% stenosis were assigned a normal/atheromatous status (0 vessel disease).
  • CAD cases included those that had at least one significant stenosis ( >50%) in any of the major coronary arteries on angiography, or those without significant stenosis but had history of MI, coronary artery bypass graft, or PCI.
  • Controls included individuals with no or minimal CAD ( ⁇ 20% stenosis) on cardiac catheterization and had no prior history of MI or CAD.
  • Angiography CAD extent was expressed as the number of coronary index vessels with >50% stenosis 66 , and as Gensini 67 , and Duke 68 severity scores. Information on ethnicity was self- re ported .
  • These tests were performed as implemented in NEMO 23 , the R-software, and STATATM software, version 10.
  • the IMT trait was logarithmically transformed prior to analysis, and covariate adjusted for age, sex and study center in the IM PROVE study and for age, sex, body mass index, and physica l exercise in the Oxfordshire Family Blood Pressure Study.
  • Lipoprotein(a) is related to the extent of lesions in the coronary vasculature and to unstable coronary syndromes.
  • Gazzaruso C Geroldi D, Garzaniti A, et al. Apolipoprotein(a) phenotypes as genetic markers of coronary atherosclerosis severity. Int J Cardiol 1998;64(3) : 277-84.
  • aneurysms a causal event or a process running in pa rallel? The Tromso study. Arterioscler Thromb Vase Biol ;30(6) : 1263-8.
  • reductase C677T mutations are not associated with chronic limb ischemia : the Linz Peripheral Arterial Disease (LIPAD) study. J Vase Surg 41, 808- 15 (2005).
  • LIPAD Linz Peripheral Arterial Disease
  • TASC TransAtlantic Inter-Society Consensus

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Abstract

Il a été découvert que certains variants génétiques indiquent un risque de maladie artérielle chez l'homme, telle que l'athérosclérose des grosses artères, l'artériopathie oblitérante, l'anévrisme de l'aorte abdominale, la coronaropathie précoce et la coronaropathie grave. La présente invention concerne des variants de ce type, et leur utilisation dans des méthodes permettant de déterminer si un sujet est susceptible ou non de développer des maladies artérielles. Ce variant est au moins un allèle d'un polymorphisme choisi parmi rs3798220 et rs 10455872. Des kits et des systèmes informatiques destinés à être utilisés dans le cadre desdites méthodes sont également décrits.
PCT/IS2012/050015 2011-11-28 2012-11-27 Variants génétiques utiles pour l'évaluation du risque de maladie artérielle Ceased WO2013080227A1 (fr)

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