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WO2023127998A1 - Composition pour prédire l'apparition de la sarcopénie chez les patients ayant subi une fracture de la hanche - Google Patents

Composition pour prédire l'apparition de la sarcopénie chez les patients ayant subi une fracture de la hanche Download PDF

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WO2023127998A1
WO2023127998A1 PCT/KR2021/020145 KR2021020145W WO2023127998A1 WO 2023127998 A1 WO2023127998 A1 WO 2023127998A1 KR 2021020145 W KR2021020145 W KR 2021020145W WO 2023127998 A1 WO2023127998 A1 WO 2023127998A1
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sarcopenia
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hip fracture
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Korean (ko)
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유준일
강양제
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Gyeongsang National University Hospital
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • 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
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    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to a composition for predicting the onset of sarcopenia in a hip fracture individual and a method for providing information for predicting whether or not the onset of sarcopenia occurs in a hip fracture individual.
  • Sarcopenia appears primarily in metabolic diseases such as diabetes, obesity, and cachexia, and in some specific diseases, including chronic renal failure, congestive heart failure, and chronic obstructive pulmonary disease.
  • sarcopenia is significantly associated with osteoporosis in the elderly population.
  • Several studies have shown that sarcopenia and osteoporosis share common risk factors and biological pathways, and that osteopenia is associated with severe physical disability and represents a serious threat in old age.
  • the combination of these two diseases has been described as a "hazardous duet" that exacerbates the negative health outcomes and adds a tendency to fall from sarcopenia to the bone fragility of people with osteoporosis.
  • the combined effects of sarcopenia and osteoporosis in the elderly represents a serious problem for them.
  • the present inventors completed the present invention with the support of the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Education, Science and Technology, MEST) (No. NRF-2019R1F1A1059208).
  • An object of the present invention is to provide a composition for predicting the onset of sarcopenia in a hip fracture subject.
  • An object of the present invention is to provide a kit for predicting the onset of sarcopenia in a hip fracture subject.
  • An object of the present invention is to provide a method for providing information for predicting the onset of sarcopenia in a hip fracture subject.
  • RUNX 1 RUNX family transcription factor 1
  • NGFR nerve growth factor receptor
  • CH3L1 Choitinase-3-like protein 1
  • BCL3 B cell lymphoma 3
  • PLA2G2A Phospholipase A2 Group IIA
  • MYBPH myosin binding protein H
  • TEP1 telomerase associated protein 1
  • SEMA6B Semaphorin 6B
  • CSPG4 chondroitin sulfate proteoglycan 4
  • ACSL5 acyl-CoA synthetase long chain family member 5
  • SLC25A3 solute carrier family 25 member 3
  • NDUFB5 NADH: ubiquinone oxidoreductase subunit B5)
  • CYC1 cytochrome c1
  • ACAT1 acetyl-CoA acetyltransferase 1
  • TCAP titin-cap
  • composition according to 1 above wherein the agent is at least one selected from the group consisting of primers, probes, antibodies, aptamers, DNA, RNA, proteins and polypeptides, the composition for predicting the onset of sarcopenia in hip fracture individuals.
  • a kit for predicting the onset of sarcopenia in a hip fracture subject comprising the composition of any one of 1 to 3 above.
  • RUNX 1 RUNX family transcription factor 1
  • NGFR nerve growth factor receptor
  • CH3L1 Choitinase-3-like protein 1
  • BCL3 B cell lymphoma 3
  • PLA2G2A Phospholipase A2 Group IIA
  • MYBPH myosin binding protein H
  • TEP1 telomerase associated protein 1
  • SEMA6B semaphorin 6B
  • CSPG4 chondroitin sulfate proteoglycan 4
  • CSPG4 acyl-CoA synthetase long chain family member 5 (ACSL5)
  • SLC25A3 solute carrier family 25 member 3
  • NDUFB5 NADH: ubiquinone oxidoreductase subunit B5)
  • CYC1 cytochrome c1
  • ACAT1 acetyl-CoA acetyltransferase 1
  • TCAP titin-cap
  • sample is one selected from the group consisting of muscle cells, muscle tissue, plasma, serum and urine.
  • composition and information providing method of the present invention can help to more effectively perform rehabilitation treatment by predicting the onset of sarcopenia in a hip fracture subject.
  • 1 is a schematic diagram showing the process of selecting a test subject.
  • FIG. 2A shows a differentially expressed gene (DEG) heatmap that clearly separates sarcopenia from normal patients
  • FIG. 2B is a swarm plot of known genes in each expression group. is shown.
  • DEG differentially expressed gene
  • Figure 3 is a DEG classification by Kegg Brite classification
  • Figure 3A shows a network-based Keg Bright classification (the size of a circle represents the number of corresponding genes, and dots represent genes corresponding to the corresponding class)
  • Figure 3B shows It represents the genetic members of the "Exosome” and "Enzyme” classes found mostly in DEGs.
  • Figure 4 shows the one-step neighbor of DEGs based on the HuRI network (among the genes circled, RUNX1, MRPL45, TCAP, TEP1, SLC25A3, NDUFB5, ACSL5, HPN are DEGs, BAG3, SNRPC, VPS37C, HGS , BAG4, NFKBID, KRTAP19-7, RHOXF2, C19orf54, BLZF1, IKZF3, PFDN5, EMD, RHBDD2, SLC10A1, TMEM14B, AQP6, SLC10A6, RETREG3, SLC35C2, BNIP3 are known network hubs of one step neighbors of the above DEGs. others indicate non-hub interactors of DEGs).
  • the present invention relates to a composition for predicting the onset of sarcopenia in a hip fracture subject.
  • the composition is RUNX 1 (RUNX family transcription factor 1), NGFR (nerve growth factor receptor), CH3L1 (Chitinase-3-like protein 1), BCL3 (B cell lymphoma 3), PLA2G2A (Phospholipase A2 Group IIA), MYBPH ( myosin binding protein H), TEP1 (telomerase associated protein 1), SEMA6B (semaphorin 6B), CSPG4 (chondroitin sulfate proteoglycan 4), ACSL5 (acyl-CoA synthetase long chain family member 5), SLC25A3 (solute carrier family 25 member 3) , NDUFB5 (NADH: ubiquinone oxidoreductase subunit B5), CYC1 (cytochrome c1), ACAT1 (acetyl-CoA acetyltransferase 1), and TCAP (titin-cap), including an agent for measuring the expression level of at least one gene selected from
  • Hip fracture refers to a fracture that occurs mainly by direct impact on the outside of the hip joint. Hip fractures are mostly caused by high-energy trauma such as falls or traffic accidents in young people, and in elderly patients due to weakened bone quality, most of them are caused by low-energy injuries such as simple falls.
  • Sarcopenia refers to a disease in which the amount, strength, and function of muscles decrease due to various reasons such as aging. Sarcopenia may be defined by Asia Working Group for Sarcopenia (AWGS) criteria.
  • AGS Asia Working Group for Sarcopenia
  • the subject may be an animal, and specifically may be a human, cow, horse, rabbit, dog, monkey, or cat, but is not limited thereto.
  • the subject may be a hip fracture patient with osteoporosis.
  • the subject may be an elderly hip fracture patient, specifically, a hip fracture patient aged 65 years or older.
  • the subject may be a female hip fracture patient.
  • composition of the present invention can be used to predict the onset of sarcopenia in a hip fracture subject, and thus can help predict the prognosis of a hip fracture subject.
  • the expression level may be an mRNA expression level of the gene or an expression level of a protein encoded by the gene.
  • the agent for measuring the expression level is limited to a substance capable of detecting RUNX 1, NGFR, CH3L1, BCL3, PLA2G2A, MYBPH, TEP1, SEMA6B, CSPG4, ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 and TCAP mRNA or its protein
  • it may be at least one selected from the group consisting of primers, probes, antibodies, aptamers, DNA, RNA, proteins, and polypeptides.
  • prediction means to guess in advance about a medical outcome.
  • the present invention provides a kit for predicting the onset of sarcopenia in a hip fracture subject comprising the above-described composition.
  • the kit measures the expression level of at least one gene selected from the group consisting of RUNX 1, NGFR, CH3L1, BCL3, PLA2G2A, MYBPH, TEP1, SEMA6B, CSPG4, ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 and TCAP described above contains the formulation.
  • the kit may include essential components required to perform ELISA in order to implement various ELISA methods such as sandwich ELISA.
  • the kit may include essential components such as a fluorescent antibody necessary for performing flow cytometry.
  • kit may be any kit known to those skilled in the art, and may be, for example, an immunochromatography strip kit, a Luminex assay kit, a protein microarray kit, an ELISA kit, a flow cytometry kit, or an immunological dot kit.
  • the kit may be a kit for implementing Western blot, immunoprecipitation assay, complement fixation assay, flow cytometry, or protein chip, and may further include additional components suitable for each assay method.
  • the present invention provides a method for providing information for predicting whether sarcopenia occurs in a hip fracture subject.
  • the information providing method is RUNX 1 (RUNX family transcription factor 1), NGFR (nerve growth factor receptor), CH3L1 (Chitinase-3-like protein 1), BCL3 (B cell lymphoma 3) measured in samples isolated from the subject , PLA2G2A (Phospholipase A2 Group IIA), MYBPH (myosin binding protein H), TEP1 (telomerase associated protein 1), SEMA6B (semaphorin 6B), CSPG4 (chondroitin sulfate proteoglycan 4), ACSL5 (acyl-CoAthetase long chain synthetase family member 5 ), at least one selected from the group consisting of SLC25A3 (solute carrier family 25 member 3), NDUFB5 (NADH: ubiquinone oxidoreductase subunit B5), CYC1 (cytochrome c1), ACAT1 (acetyl-CoA acetyltransferase 1)
  • Hip fracture, sarcopenia, subject, expression level, and prediction may be within the above range, but are not limited thereto.
  • the subject may be an individual with a fractured hip joint.
  • the subject may be an individual who has experienced hip fracture surgery or is scheduled to undergo hip fracture surgery.
  • a sample isolated from a subject may be selected from the group consisting of muscle cells, muscle tissue, plasma, serum, and urine.
  • Controls can be normal individuals or hip fracture patients.
  • a control group may be a hip fracture patient without sarcopenia.
  • a control group may be a hip fracture patient with osteoporosis without sarcopenia.
  • the method of providing information is that if the expression level of at least one gene selected from the group consisting of RUNX 1, NGFR, CH3L1, BCL3 and PLA2G2A is higher than the expression level in the control group, sarcopenia compared to the control group is likely to occur. To provide information Further steps may be included.
  • the inventors confirmed that the expression level of at least one gene selected from the group consisting of RUNX 1, NGFR, CH3L1, BCL3 and PLA2G2A measured in a sample isolated from the subject correlated positively with the possibility of developing sarcopenia did Therefore, if the expression level of at least one gene selected from the group consisting of RUNX 1, NGFR, CH3L1, BCL3 and PLA2G2A measured in a sample isolated from the subject is higher than the expression level in the control group, the possibility of developing sarcopenia compared to the control group is high. can provide information.
  • the information providing method further includes the step of providing information that, when the expression level of at least one gene selected from the group consisting of MYBPH, TEP1, SEMA6B, and CSPG4 is higher than that in the control group, the possibility of developing sarcopenia is high compared to the control group.
  • the expression level of at least one gene selected from the group consisting of MYBPH, TEP1, SEMA6B, and CSPG4 is higher than that in the control group, the possibility of developing sarcopenia is high compared to the control group.
  • the present inventors confirmed that the expression level of at least one gene selected from the group consisting of MYBPH, TEP1, SEMA6B, and CSPG4 measured in a sample isolated from a subject has a positive correlation with the possibility of developing sarcopenia. Therefore, if the expression level of at least one gene selected from the group consisting of MYBPH, TEP1, SEMA6B and CSPG4 measured in a sample isolated from the subject is higher than the expression level in the control group, it provides information that the possibility of developing sarcopenia compared to the control group is high. can do.
  • the method of providing information is that if the expression level of at least one gene selected from the group consisting of ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 and TCAP is lower than the expression level in the control group, the possibility of developing sarcopenia compared to the control group is high.
  • the step of providing may be further included.
  • the present inventors found that the expression level of at least one gene selected from the group consisting of ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 and TCAP measured in a sample isolated from a subject has a negative correlation with the possibility of developing sarcopenia Confirmed. Therefore, if the expression level of at least one gene selected from the group consisting of ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 and TCAP measured in a sample isolated from the subject is lower than the expression level in the control group, there is a possibility of developing sarcopenia compared to the control group. It can provide information that will be high.
  • the information providing method is at least one selected from the group consisting of RUNX 1, NGFR, CH3L1, BCL3, PLA2G2A, MYBPH, TEP1, SEMA6B, CSPG4, ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 and TCAP in a sample isolated from the subject A step of measuring the expression level of the gene may be further included.
  • the step of measuring the expression level of the gene may be performed by treating the sample with an agent for measuring the mRNA expression level of the gene to be measured or the expression level of the protein encoded by the gene.
  • RT-PCR Reverse transcriptase polymerase reaction
  • RPA RNase protection assay
  • Northern blotting and DNA chips may be used, but are not limited thereto.
  • Analysis methods for measuring protein expression include western blotting, enzyme linked immunosorbent assay (ELISA), radioimmunoassay, radioimmunodiffusion, and Ouchterlony immunodiffusion method. , Rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay, flow cytometry (Fluorescence Activated Cell Sorter, FACS), protein chip, etc. , but is not limited thereto.
  • the patient group included subjects aged 65 years or older who underwent hip fracture surgery.
  • 323 patients with hip fracture (HF) confirmed from May 2017 to December 2019, 162 patients with hip fracture (excluding high energy trauma and non-osteoporosis) (90 patients with non-sarcopenia and 72 patients with sarcopenia) were included in the final analysis.
  • HF hip fracture
  • 162 patients with hip fracture excluding high energy trauma and non-osteoporosis
  • HGS hand grip strength
  • the bottom 10% was set as the patient group, except for patients with poor tissue quality, the sarcopenia group and the proximal muscle group.
  • Six and five patients were selected as the saponification group, respectively.
  • each patient with HGS value in the top 20% and bottom 20% was set as a control group and patient group. Excluding patients with poor tissue quality, 12 patients and 12 patients in the sarcopenia group and the non-sarcopenia group, respectively, were selected. Four patients were selected (Fig. 1).
  • Muscle samples were collected through a 5 ⁇ 5 ⁇ 3 mm gluteus maximus obtained from a surgical opening. Tissues were stored at -80°C at Tissue-Tek (Miles, Elkhart, IN, USA).
  • Body composition was measured by whole-body DXA (DPX-NT; GE Medical Systems Lunar, Madison, WI, USA). Bone mineral content, fat mass, and lean soft tissue mass (lean mass) were separately measured for each body part including arms and legs. The lean soft tissue mass of the arms and legs was approximately equal to the skeletal muscle mass. Since absolute muscle mass is correlated with height, the skeletal muscle mass index (SMI) was calculated with the following formula: lean mass [kg]/height 2 [m 2 ], which is It is directly similar to body mass index (BMI) (BMI: weight [kg]/height 2 [m 2 ]). Arm SMI was defined as “arm lean mass [kg]/height 2 [m 2 ]”. Leg SMI was defined as “lean mass [kg]/height 2 [m 2 ]”. Limb SMI (Appendicular SMI) was defined as the sum of arm SMI and leg SMI.
  • BMI body mass index
  • Muscle strength was evaluated by grip strength using an analogue dynamometer (TK 5001 Grip-A, Takei, Tokyo, Japan). In a sitting position, with the shoulder attached to the body, the elbow bent at 90°, and the wrist maintaining a neutral posture (0°), the grip force giving the maximum force was measured.
  • Sarcopenia is defined as low muscle strength (grip strength less than 18 kg for women and less than 28 kg for men) and reduced muscle mass (SMI less than 5.4 kg/m 2 for women) according to the Asia Working Group for Sarcopenia (AWGS) standards. male SMI less than 7.0 kg/m 2 ).
  • Bone mineral content (BMC) and bone mineral density (BMD) of the total femur, femoral neck, and lumbar spine (L1-L4) were measured using dual energy X-rays. Absorbance was measured by a trained technician using an absorptiometry (DXA, dual-energy X-ray absorptiometry, Lunar Prodigy, GE Healthcare, Madison, WI, USA). Osteoporosis was diagnosed using the T-score criteria of the World Health Organization (WHO) as supplied by the DXA manufacturer (Japan): normal, osteopenic, classified as osteoporosis.
  • WHO World Health Organization
  • Osteoporosis was defined as a BMD 2.5 standard deviation (SD) lower than the peak bone mass of a young, healthy, gender- and race-matched reference population according to the WHO diagnostic classification.
  • SD standard deviation
  • SMI standard deviation
  • T-score ⁇ -2.5 and low SMI normal (high T-score and high SMI).
  • MNA Mini nutritional assessment
  • the screening portion consists of questions about food intake, weight loss, mobility, stress, neuropsychological problems, and body mass index (BMI). did The evaluation part consisted of detailed questions about self-views on nutrition and health status, mid-arm and calf circumference measurements.
  • a malnourished patient was defined as an MNA score of less than 17 points.
  • the library was prepared for 100 bp paired-end sequencing using the TruSeq Stranded mRNA Sample Preparation Kit (Illumina, CA, USA). That is, mRNA molecules were purified and fragmented from 1 ⁇ g of total RNA using oligo(dT) magnetic beads. Fragmented mRNA was synthesized into single-stranded cDNA through random hexamer priming. This was applied as a template for second-strand synthesis to prepare double-stranded cDNA. After sequential processes of end repair, A-tailing, and adapter ligation, the cDNA library was amplified by PCR (Polymerase Chain Reaction).
  • the quality of the cDNA library was assessed with an Agilent 2100 BioAnalyzer (Agilent, CA, USA). Libraries were quantified using the KAPA library quantification kit (Kapa Biosystems, MA, USA) according to the manufacturer's library quantification protocol. After cluster amplification of the denatured template, sequencing was performed with paired-end (2 ⁇ 100 bp) using the Illumina HiSeq platform sequencer (Illumina, CA, USA).
  • Low quality reads were identified according to the following criteria; If more than 10% of the missing bases are included, if more than 40% of the bases with a quality score of less than 20 are included, if the average quality score of each read is less than 20.
  • the entire filtering process was performed using an in-house script. Filtered short reads were mapped to the human reference coding sequence (CDS), version GRCh38 using the software Kallisto. Using Deseq2 to extract a set of differentially expressed genes (DEGs) that differentiate between sarcopenia and non-sarcopenia groups carefully defined by clinical observation through gene expression counts did to do Candidate genes were selected based on fold change and adjusted p-values.
  • DEGs differentially expressed genes
  • cDNA was prepared with forward and reverse primers for HPN of RUNX1, SLC25A3, BCL3, CHI3L1, MYBPH, ACSL5, NDUFB5, NGFR, PLAG2A, CSPG4, SEMA6B, TEP1, AC068506.1, THBS1, ACAT1, CYC1, TCAP in 384-well plates.
  • 384-well plate MicroAmp® 384-well Reaction Plate with Barcode with Power SYBR Green PCR Master Mix (Applied Biosystems, Warrington, UK), Applied Biosystems, Foster City, CA, USA). Each sample was measured 3 times.
  • GAPDH was amplified by real-time RT-PCR (qPCR) as a housekeeping gene to normalize mRNA levels between samples. Analysis was performed using the ViiATM7 real-time PCR system (Applied Biosystems, USA). The sequences of the primers used in the experiment are shown in Table 1. The cycle threshold value measured after the experiment was analyzed by the relative quantification 2 - ⁇ C(T) method.
  • RNAseq The collected samples were subjected to RNAseq using the Illumina platform. A total of 11 samples obtained from sarcopenia and non-sarcopenia groups were sequenced (Tables 3 to 5). Based on the number of reads generated and the mapping rate, we determined that the RNAseq results were reliable for downstream analysis (Table 6). The average amount of each sample read was 6.4 GB. More than 97% of the sequences were above the Q30 base quality score. Sequences were quantified by gene expression using Kallisto software.
  • the expression patterns of DEGs were classified into three groups. Genes in group 1 showed increased expression in sarcopenia patients, especially in the first two cases, whereas pharopenia patients showed low expression levels. Genes in group 2 showed high expression in all sarcopenia patients compared to low expression in sarcopenia patients. On the other hand, the expression of genes in group 3 was increased in patients with sarcopenia. For functional annotation, DEGs were classified by the Kegg Brite database (Fig. 3A).
  • ACSL5 showed a clear upregulation, whereas ACAT1 showed a downregulation in sarcopenia patients (Fig. 2B).
  • ACAT1 showed a downregulation in sarcopenia patients (Fig. 2B).
  • ACSL5 has a hub gene as a HuRI (Human Reference Interactome)-based interaction partner ( Figure 4). The hub interactors of ACSL5 provide insight into the link between ACSL5 perturbations and sarcopenia.
  • HuRI Human Reference Interactome
  • Solute carrier (SLC) families transmembrane protein 14 B (TMEM14B) and aquaporin 6 (AQP6) imply transport-related protein activity may be associated with sarcopenia.
  • SLC25A3 Another SLC family, SLC25A3, showed significant downregulation in patients with sarcopenia (Fig. 2B).
  • HLA-F and HLA-DR3B showed differential expression and were mapped to the “Phagosome” (ko04145) pathway of the Kegg Pathway (Fig. 2B).

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Abstract

La présente invention concerne une composition permettant de prédire l'apparition de la sarcopénie chez les patients ayant subi une fracture de la hanche. Plus particulièrement, en comprenant un agent qui mesure le niveau d'expression d'un gène choisi dans le groupe constitué de RUNX 1, NGFR, CH3L1, BCL3, PLA2G2A, MYBPH, TEP1, SEMA6B, CSPG4, ACSL5, SLC25A3, NDUFB5, CYC1, ACAT1 et TCAP, la présente invention permet au traitement de rééducation d'être plus efficace pour les patients ayant subi une fracture de la hanche.
PCT/KR2021/020145 2021-12-29 2021-12-29 Composition pour prédire l'apparition de la sarcopénie chez les patients ayant subi une fracture de la hanche Ceased WO2023127998A1 (fr)

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CN119125571A (zh) * 2024-08-19 2024-12-13 安徽医科大学 用于类风湿关节炎诊断的生物标志物及其应用

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KANG YANG-JAE, YOO JUN-IL, BAEK KYUNG-WAN: "Differential gene expression profile by RNA sequencing study of elderly osteoporotic hip fracture patients with sarcopenia", JOURNAL OF ORTHOPAEDIC TRANSLATION, vol. 29, 1 July 2021 (2021-07-01), pages 10 - 18, XP093075894, ISSN: 2214-031X, DOI: 10.1016/j.jot.2021.04.009 *
KIM JIN A., VETRIVEL PREETHI, KIM SEONG MIN, HA SANG EUN, KIM HUN HWAN, BHOSALE PRITAM BHAGWAN, HEO JEONG DOO, LEE WON SUP, SENTHI: "Quantitative Proteomics Analysis for the Identification of Differential Protein Expression in Calf Muscles between Young and Old SD Rats Using Mass Spectrometry", ACS OMEGA, ACS PUBLICATIONS, US, vol. 6, no. 11, 23 March 2021 (2021-03-23), US , pages 7422 - 7433, XP093075897, ISSN: 2470-1343, DOI: 10.1021/acsomega.0c05821 *
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CN119125571A (zh) * 2024-08-19 2024-12-13 安徽医科大学 用于类风湿关节炎诊断的生物标志物及其应用

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