Biomarker for predicting disease onset risk

Abstract

Provided is a biomarker for predicting disease onset risk. This biomarker for predicting disease onset risk comprises at least one selected from the group consisting of: the single nucleotide polymorphism rs200137244 in the SIGLEC1 gene, the single nucleotide polymorphism rs143664589 in the SIGLEC1 gene, the single nucleotide polymorphism rs111336308 in the SIGLEC1 gene, the single nucleotide polymorphism rs3746636 in the SIGLEC1 gene, the single nucleotide polymorphism rs76943436 in the SIGLEC4 gene, the single nucleotide polymorphism rs11084810 in the SIGLEC4 gene, the single nucleotide polymorphism rs1807124 in the SIGLEC5 gene, the single nucleotide polymorphism rs2305773 in the SIGLEC6 gene, the single nucleotide polymorphism rs76001696 in the SIGLEC6 gene, the single nucleotide polymorphism rs2305770 in the SIGLEC8 gene, the single nucleotide polymorphism rs7258951 in the SIGLEC10 gene, the single nucleotide polymorphism rs145769059 in the SIGLEC10 gene, the single nucleotide polymorphism rs200296439 in the SIGLEC11 gene, the single nucleotide polymorphism rs74354979 in the SIGLEC12 gene, the single nucleotide polymorphism rs111981406 in the SIGLEC14 gene, the single nucleotide polymorphism rs71353353 in the SIGLEC16 gene, and the single nucleotide polymorphism rs544574549 in the SIGLEC16 gene.

Description

Biomarkers for predicting disease risk

[0001] The present invention relates to a biomarker for predicting the risk of developing a disease.

[0002] Genetic testing is becoming more widespread, and with growing health awareness, there is a desire to utilize genetic testing, for example, for personalized medical care based on disease risk.

[0003] Siglecs (SIGLECs) are a family of lectins (SIGLECs 1-16) that recognize sialic acid-containing sugar chains. They are a group of molecules that have evolved to have a unique human expression pattern and function. SIGLECs are primarily expressed in immune system cells and are involved in maintaining homeostasis by positively and negatively regulating tissue damage and inflammatory responses caused by excessive immune cell activation. Research is currently underway worldwide to determine how genetic polymorphisms in SIGLECs affect protein function and lead to disease development. Patent Document 1 reports a technology for determining treatment strategies for infectious diseases by detecting certain polymorphisms in the SIGLEC14 gene.

[0004] Japanese Patent Application Laid-Open No. 2010-035551

[0005] An objective of the present invention is to provide a biomarker for predicting the risk of developing a disease.

[0006] The present inventors have conducted intensive research in light of the above-mentioned problems, and as a result have discovered a single nucleotide polymorphism of rs200137244 in the SIGLEC1 gene, a single nucleotide polymorphism of rs143664589 in the SIGLEC1 gene, a single nucleotide polymorphism of rs111336308 in the SIGLEC1 gene, a single nucleotide polymorphism of rs3746636 in the SIGLEC1 gene, a single nucleotide polymorphism of rs76943436 in the SIGLEC4 gene, a single nucleotide polymorphism of rs11084810 in the SIGLEC5 gene, a single nucleotide polymorphism of rs1807124 in the SIGLEC6 gene, a single nucleotide polymorphism of rs2305773 in the SIGLEC6 gene, a single nucleotide polymorphism of rs76001696 in the SIGLEC8 gene, a single nucleotide polymorphism of rs1807124 in the SIGLEC5 gene, a single nucleotide polymorphism of rs2305773 in the SIGLEC6 gene, a single nucleotide polymorphism of rs76001696 in the SIGLEC8 gene, a single nucleotide polymorphism of rs1807124 in the SIGLEC6 gene, a single nucleotide polymorphism of rs1807124 in the SIGLEC7 gene, a single nucleotide polymorphism of rs2305773 in the SIGLEC7 gene, a single nucleotide polymorphism of rs76001696 in the SIGLEC8 gene, a single nucleotide polymorphism of rs1807124 in the SIGLEC9 gene, a single nucleotide polymorphism of rs1807124 in the SIGLEC9 gene, a single nucleotide polymorphism of The inventors have found that the above-mentioned problems can be solved by a biomarker for predicting the risk of disease onset, comprising at least one selected from the group consisting of rs2305770, a single nucleotide polymorphism of the SIGLEC10 gene, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene. Based on this finding, the inventors have conducted further research and completed the present invention. That is, the present invention encompasses the following aspects.

[0007] Item 1. Single nucleotide polymorphism rs200137244 of the SIGLEC1 gene, single nucleotide polymorphism rs143664589 of the SIGLEC1 gene, single nucleotide polymorphism rs111336308 of the SIGLEC1 gene, single nucleotide polymorphism rs3746636 of the SIGLEC1 gene, single nucleotide polymorphism rs76943436 of the SIGLEC4 gene, single nucleotide polymorphism rs11084810 of the SIGLEC5 gene, single nucleotide polymorphism rs1807124 of the SIGLEC6 gene, single nucleotide polymorphism rs2305773 of the SIGLEC6 gene, single nucleotide polymorphism rs76001696 of the SIGLEC8 gene a single nucleotide polymorphism of the SIGLEC10 gene; rs2305770, a single nucleotide polymorphism of the SIGLEC10 gene; rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene; rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene; rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene; rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene; rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene; rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene; and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

[0008] Item 2. For rs200137244, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of gastritis and allergic rhinitis; for rs143664589, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of bulimia nervosa (binge eating) and multiple chemical sensitivity; for rs111336308, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of anorexia nervosa, ulcerative colitis, bulimia nervosa, and mandibular protrusion; for rs3746636, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of heart failure, hepatitis C, myocardial infarction, and angina pectoris; and for rs76943436, a single nucleotide polymorphism in the SIGLEC4 gene, the disease is at least one selected from the group consisting of gallstones, gastric ulcer, hives, gastritis, and periodontal disease. For the single nucleotide polymorphism rs11084810 of the SIGLEC4 gene, the disease is at least one selected from the group consisting of heart failure, subarachnoid hemorrhage, gout, scoliosis, colorectal cancer, myocardial infarction, angina pectoris, and head trauma accompanied by loss of consciousness; for the single nucleotide polymorphism rs1807124 of the SIGLEC5 gene, the disease is at least one selected from the group consisting of endometriosis, allergic conjunctivitis, and iron deficiency anemia; for the single nucleotide polymorphism rs2305773 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of chronic sinusitis, myocardial infarction, angina pectoris, and hearing loss; and for the single nucleotide polymorphism rs76001696 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of atopic dermatitis and hypertension. For the single nucleotide polymorphism rs2305770 of the SIGLEC8 gene, the disease is at least one selected from the group consisting of iron deficiency anemia and myopia; for the single nucleotide polymorphism rs7258951 of the SIGLEC10 gene, the disease is at least one selected from the group consisting of collagen disease, ADHD, ventricular fibrillation, type 1 diabetes, fractures, ureteral stones, and kidney stones; for the single nucleotide polymorphism rs145769059 of the SIGLEC10 gene, the disease is migraine;For the single nucleotide polymorphism rs200296439 of the SIGLEC11 gene, the disease is a collagen disease; for the single nucleotide polymorphism rs74354979 of the SIGLEC12 gene, the disease is at least one selected from the group consisting of head trauma accompanied by loss of consciousness, chronic bronchitis, corneal disease, food allergy, hepatitis C, and migraine; for the single nucleotide polymorphism rs111981406 of the SIGLEC14 gene, the disease is at least one selected from the group consisting of contact dermatitis, knee osteoarthritis, prostate cancer, hearing loss, ureteral stones, kidney stones, and gastritis; and for the single nucleotide polymorphism rs71353353 of the SIGLEC16 gene, the disease is at least one selected from the group consisting of congenital hip dislocation, ventricular fibrillation, autoimmune disease, pancreatitis, uterine cancer, and cerebral infarction; Item 2. The biomarker according to Item 1, wherein, for rs544574549, which is a single nucleotide polymorphism in the SIGLEC16 gene, the disease is at least one selected from the group consisting of systemic lupus erythematosus, bulimia nervosa, cerebral infarction, and macular degeneration.

[0009] Section 3. (1) In genomic DNA of a biological sample collected from a subject, a single nucleotide polymorphism of the SIGLEC1 gene, rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene, rs143664589, a single nucleotide polymorphism of the SIGLEC1 gene, rs111336308, a single nucleotide polymorphism of the SIGLEC1 gene, rs3746636, a single nucleotide polymorphism of the SIGLEC4 gene, rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene, rs11084810, a single nucleotide polymorphism of the SIGLEC5 gene, rs1807124, a single nucleotide polymorphism of the SIGLEC6 gene, rs2305773, and a single nucleotide polymorphism of the SIGLEC6 gene, 96. A method for detecting a single nucleotide polymorphism, comprising the step of examining the presence or absence of at least one polymorphism selected from the group consisting of rs2305770, a single nucleotide polymorphism of the SIGLEC8 gene, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

[0010] Section 4. (1) In genomic DNA of a biological sample collected from a subject, a single nucleotide polymorphism of the SIGLEC1 gene, rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene, rs143664589, a single nucleotide polymorphism of the SIGLEC1 gene, rs111336308, a single nucleotide polymorphism of the SIGLEC1 gene, rs3746636, a single nucleotide polymorphism of the SIGLEC4 gene, rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene, rs11084810, a single nucleotide polymorphism of the SIGLEC5 gene, rs1807124, a single nucleotide polymorphism of the SIGLEC6 gene, rs2305773, and a single nucleotide polymorphism of the SIGLEC6 gene, rs7600169 6. A method for testing the risk of developing a disease, comprising a step of examining the presence or absence of at least one polymorphism selected from the group consisting of rs2305770, a single nucleotide polymorphism of the SIGLEC8 gene, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

[0011] Item 5. The testing method according to Item 4, further comprising: (2a) determining that the subject has a high risk of developing a disease if at least one of the single nucleotide polymorphisms is detected in the step (1), and / or (2b) determining that the subject has a low risk of developing a disease if at least one of the single nucleotide polymorphisms is not detected in the step (1).

[0012] Item 6. For rs200137244, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of gastritis and allergic rhinitis; for rs143664589, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of bulimia nervosa (binge eating) and multiple chemical sensitivity; for rs111336308, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of anorexia nervosa, ulcerative colitis, bulimia nervosa, and mandibular protrusion; for rs3746636, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of heart failure, hepatitis C, myocardial infarction, and angina pectoris; and for rs76943436, a single nucleotide polymorphism in the SIGLEC4 gene, the disease is at least one selected from the group consisting of gallstones, gastric ulcer, hives, gastritis, and periodontal disease. For the single nucleotide polymorphism rs11084810 of the SIGLEC4 gene, the disease is at least one selected from the group consisting of heart failure, subarachnoid hemorrhage, gout, scoliosis, colorectal cancer, myocardial infarction, angina pectoris, and head trauma accompanied by loss of consciousness; for the single nucleotide polymorphism rs1807124 of the SIGLEC5 gene, the disease is at least one selected from the group consisting of endometriosis, allergic conjunctivitis, and iron deficiency anemia; for the single nucleotide polymorphism rs2305773 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of chronic sinusitis, myocardial infarction, angina pectoris, and hearing loss; and for the single nucleotide polymorphism rs76001696 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of atopic dermatitis and hypertension. For the single nucleotide polymorphism rs2305770 of the SIGLEC8 gene, the disease is at least one selected from the group consisting of iron deficiency anemia and myopia; for the single nucleotide polymorphism rs7258951 of the SIGLEC10 gene, the disease is at least one selected from the group consisting of collagen disease, ADHD, ventricular fibrillation, type 1 diabetes, fractures, ureteral stones, and kidney stones; for the single nucleotide polymorphism rs145769059 of the SIGLEC10 gene, the disease is migraine;For the single nucleotide polymorphism rs200296439 of the SIGLEC11 gene, the disease is a collagen disease; for the single nucleotide polymorphism rs74354979 of the SIGLEC12 gene, the disease is at least one selected from the group consisting of head trauma accompanied by loss of consciousness, chronic bronchitis, corneal disease, food allergy, hepatitis C, and migraine; for the single nucleotide polymorphism rs111981406 of the SIGLEC14 gene, the disease is at least one selected from the group consisting of contact dermatitis, knee osteoarthritis, prostate cancer, hearing loss, ureteral stones, kidney stones, and gastritis; and for the single nucleotide polymorphism rs71353353 of the SIGLEC16 gene, the disease is at least one selected from the group consisting of congenital hip dislocation, ventricular fibrillation, autoimmune disease, pancreatitis, uterine cancer, and cerebral infarction; Item 6. The method for testing according to Item 4 or 5, wherein, for rs544574549, which is a single nucleotide polymorphism in the SIGLEC16 gene, the disease is at least one selected from the group consisting of systemic lupus erythematosus, bulimia nervosa, cerebral infarction, and macular degeneration.

[0013] Item 7. rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene, rs143664589, a single nucleotide polymorphism of the SIGLEC1 gene, rs111336308, a single nucleotide polymorphism of the SIGLEC1 gene, rs3746636, a single nucleotide polymorphism of the SIGLEC1 gene, rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene, rs11084810, a single nucleotide polymorphism of the SIGLEC5 gene, rs1807124, a single nucleotide polymorphism of the SIGLEC6 gene, rs2305773, a single nucleotide polymorphism of the SIGLEC6 gene, rs76001696, and a single nucleotide polymorphism of the SIGLEC8 gene, Item 770, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene. A test agent for use in the detection method of Item 3 and / or the test method of any one of Items 4 to 7, comprising at least one detection agent selected from the group consisting of:

[0014] The present invention can provide a biomarker for predicting the risk of developing a disease, a method for detecting a specific single nucleotide polymorphism in the SIGLEC6 gene, a method for testing the risk of developing a disease using the detection, and a test agent for use in these detection or testing methods.

[0015] In this specification, the expressions "contain" and "comprise" include the concepts of "contain", "include", "consist essentially of" and "consist only of".

[0016] In one aspect, the present invention relates to a single nucleotide polymorphism of rs200137244 in the SIGLEC1 gene, rs143664589 in the SIGLEC1 gene, rs111336308 in the SIGLEC1 gene, rs3746636 in the SIGLEC1 gene, rs76943436 in the SIGLEC4 gene, rs11084810 in the SIGLEC4 gene, rs1807124 in the SIGLEC5 gene, rs2305773 in the SIGLEC6 gene, rs76001696 in the SIGLEC6 gene, and rs2305 in the SIGLEC8 gene. 770, rs7258951 which is a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059 which is a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439 which is a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979 which is a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406 which is a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353 which is a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549 which is a single nucleotide polymorphism of the SIGLEC16 gene (herein also referred to as the "biomarker of the present invention").

[0017] The single nucleotide polymorphism rs200137244 in the SIGLEC1 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs200137244. rs200137244 is a polymorphism present in the human SIGLEC1 gene region, specifically, a polymorphism at the 3902nd base from the 5' end of SEQ ID NO: 7, which represents the wild-type amino acid coding sequence of the SIGLEC1 gene, in which the wild-type base T is mutated to the C base.

[0018] The single nucleotide polymorphism rs143664589 in the SIGLEC1 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs143664589. rs143664589 is a polymorphism present in the human SIGLEC1 gene region, specifically, a polymorphism at the 4138th base from the 5' end of SEQ ID NO: 7, which represents the wild-type amino acid coding sequence of the SIGLEC1 gene, in which the wild-type base T is mutated to the C base.

[0019] The single nucleotide polymorphism rs111336308 in the SIGLEC1 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs111336308. rs111336308 is a polymorphism present in the human SIGLEC1 gene region, specifically, a polymorphism at the 583rd base from the 5' end of SEQ ID NO: 7, which shows the wild-type amino acid coding sequence of the SIGLEC1 gene, in which the wild-type base G is mutated to the base A.

[0020] The single nucleotide polymorphism rs3746636 in the SIGLEC1 gene is an SNP registered under the accession number rs3746636 in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ). rs3746636 is a polymorphism present in the human SIGLEC1 gene region, specifically, a polymorphism at the 4004th base from the 5' end of SEQ ID NO: 7, which represents the wild-type amino acid coding sequence of the SIGLEC1 gene, in which the wild-type base C is mutated to base A.

[0021] The single nucleotide polymorphism rs76943436 in the SIGLEC4 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs76943436. rs76943436 is a polymorphism present in the human SIGLEC4 gene region, specifically, a polymorphism at the 905th base from the 5' end of SEQ ID NO: 1, which represents the wild-type amino acid coding sequence of the SIGLEC4 gene, in which the wild-type base T has been mutated to the base A.

[0022] The single nucleotide polymorphism rs11084810 in the SIGLEC4 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs11084810. rs11084810 is a polymorphism present in the human SIGLEC4 gene region, specifically, a polymorphism at the 604th base from the 5' end of SEQ ID NO: 1, which represents the wild-type amino acid coding sequence of the SIGLEC4 gene, in which the wild-type base C has been mutated to base A.

[0023] The single nucleotide polymorphism rs1807124 in the SIGLEC5 gene is an SNP registered under the accession number rs1807124 in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ). rs1807124 is a polymorphism present in the human SIGLEC5 gene region, specifically, a polymorphism at the 643rd base from the 5' end of SEQ ID NO: 8, which represents the wild-type amino acid coding sequence of the SIGLEC5 gene, in which the wild-type base A is mutated to the base G.

[0024] The single nucleotide polymorphism rs2305773 in the SIGLEC6 gene is an SNP registered under the registration number rs2305773 in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ). rs2305773 is a polymorphism present in the human SIGLEC6 gene region, specifically, a polymorphism at the 169th base from the 5' end of SEQ ID NO: 2, which represents the wild-type amino acid coding sequence of the SIGLEC6 gene, in which the wild-type base C is mutated to the base G.

[0025] The single nucleotide polymorphism rs76001696 in the SIGLEC6 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs76001696. rs76001696 is a polymorphism present in the human SIGLEC6 gene region, specifically, a polymorphism at the 64th base from the 5' end of SEQ ID NO: 2, which represents the wild-type amino acid coding sequence of the SIGLEC6 gene, in which the wild-type base G is mutated to the base C.

[0026] The single nucleotide polymorphism rs2305770 in the SIGLEC8 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs2305770. rs2305770 is a polymorphism present in the human SIGLEC8 gene region, specifically, a polymorphism at the 97th base from the 5' end of SEQ ID NO: 3, which represents the wild-type amino acid coding sequence of the SIGLEC8 gene, in which the wild-type base G is mutated to the base A.

[0027] The single nucleotide polymorphism rs7258951 in the SIGLEC10 gene is an SNP registered under the accession number rs7258951 in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ). rs7258951 is a polymorphism present in the human SIGLEC10 gene region, specifically, a polymorphism at the 913th base from the 5' end of SEQ ID NO: 4, which represents the wild-type amino acid coding sequence of the SIGLEC10 gene, in which the wild-type base C is mutated to base A.

[0028] The single nucleotide polymorphism rs145769059 in the SIGLEC10 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs145769059. rs145769059 is a polymorphism present in the human SIGLEC10 gene region, specifically, a polymorphism at the 323rd base from the 5' end of SEQ ID NO: 4, which represents the wild-type amino acid coding sequence of the SIGLEC10 gene, in which the wild-type base C is mutated to the base T.

[0029] The single nucleotide polymorphism rs200296439 in the SIGLEC11 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs200296439. rs200296439 is a polymorphism present in the human SIGLEC11 gene region, specifically, a polymorphism at the 85th base from the 5' end of SEQ ID NO: 5, which represents the wild-type amino acid coding sequence of the SIGLEC11 gene, in which the wild-type base A is mutated to the base G.

[0030] The single nucleotide polymorphism rs74354979 in the SIGLEC12 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs74354979. rs74354979 is a polymorphism present in the human SIGLEC12 gene region, specifically, a polymorphism at the 229th base from the 5' end of SEQ ID NO: 9, which represents the wild-type amino acid coding sequence of the SIGLEC12 gene, in which the wild-type base G is mutated to the base A.

[0031] The single nucleotide polymorphism rs111981406 in the SIGLEC14 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs111981406. rs111981406 is a polymorphism present in the human SIGLEC14 gene region, specifically a polymorphism at the 643rd base from the 5' end of SEQ ID NO: 10, which represents the wild-type amino acid coding sequence of the SIGLEC14 gene, in which the wild-type base G is mutated to the base A.

[0032] The single nucleotide polymorphism rs71353353 in the SIGLEC16 gene is an SNP registered in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ) under the registration number rs71353353. rs71353353 is a polymorphism present in the human SIGLEC16 gene region, specifically, a polymorphism at the 251st base from the 5' end of SEQ ID NO: 6, which represents the wild-type amino acid coding sequence of the SIGLEC16 gene, in which the wild-type base A is mutated to base C.

[0033] The single nucleotide polymorphism rs544574549 in the SIGLEC16 gene is an SNP registered under the registration number rs544574549 in the NCBI SNP Database (http: / / www.ncbi.nlm.nih.gov / snp / ). rs544574549 is a polymorphism present in the human SIGLEC16 gene region, specifically, a polymorphism at the 349th base from the 5' end of SEQ ID NO: 6, which represents the wild-type amino acid coding sequence of the SIGLEC16 gene, in which the wild-type base T is mutated to the C base.

[0034] The risk of developing a disease includes not only the possibility of developing a disease in the future even if one does not currently have the disease, but also the possibility of currently having the disease. The biomarkers of the present invention can be used to predict whether or not there is a risk of developing a disease.

[0035] In a more specific preferred embodiment of the present invention, for rs200137244, which is a single nucleotide polymorphism of the SIGLEC1 gene, the disease is at least one selected from the group consisting of gastritis and allergic rhinitis; for rs143664589, which is a single nucleotide polymorphism of the SIGLEC1 gene, the disease is at least one selected from the group consisting of bulimia nervosa (binge eating) and multiple chemical sensitivity; for rs111336308, which is a single nucleotide polymorphism of the SIGLEC1 gene, the disease is at least one selected from the group consisting of anorexia nervosa, ulcerative colitis, bulimia nervosa, and mandibular protrusion; and for rs3746636, which is a single nucleotide polymorphism of the SIGLEC1 gene, the disease is at least one selected from the group consisting of heart failure, hepatitis C, myocardial infarction, and angina pectoris. For rs76943436, a single nucleotide polymorphism in the SIGLEC4 gene, the disease is at least one selected from the group consisting of gallstones, gastric ulcers, hives, gastritis, and periodontal disease (preferably gallstones, gastric ulcers, hives, and gastritis, more preferably gallstones and gastric ulcers, even more preferably gallstones); for rs11084810, a single nucleotide polymorphism in the SIGLEC4 gene, the disease is at least one selected from the group consisting of heart failure, subarachnoid hemorrhage, gout, scoliosis, colorectal cancer, myocardial infarction, angina pectoris, and head trauma accompanied by loss of consciousness; for rs1807124, a single nucleotide polymorphism in the SIGLEC5 gene, the disease is at least one selected from the group consisting of endometriosis, allergic conjunctivitis, and iron deficiency anemia; For the single nucleotide polymorphism rs2305773 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of chronic sinusitis, myocardial infarction, angina pectoris, and hearing loss (preferably chronic sinusitis, myocardial infarction, and angina pectoris); for the single nucleotide polymorphism rs76001696 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of atopic dermatitis and hypertension; for the single nucleotide polymorphism rs2305770 of the SIGLEC8 gene, the disease is at least one selected from the group consisting of iron deficiency anemia and myopia (preferably iron deficiency anemia);For rs7258951, a single nucleotide polymorphism in the SIGLEC10 gene, the disease is at least one selected from the group consisting of collagen disease, ADHD (attention deficit hyperactivity disorder), ventricular fibrillation, type 1 diabetes, fracture, ureteral stones, and kidney stones (preferably collagen disease, ADHD, and ventricular fibrillation, more preferably collagen disease and ADHD); for rs145769059, a single nucleotide polymorphism in the SIGLEC10 gene, the disease is migraine; for rs200296439, a single nucleotide polymorphism in the SIGLEC11 gene, the disease is collagen disease; for rs74354979, a single nucleotide polymorphism in the SIGLEC12 gene, the disease is at least one selected from the group consisting of head trauma accompanied by loss of consciousness, chronic bronchitis, corneal disease, food allergy, hepatitis C, and migraine; For the single nucleotide polymorphism rs111981406 of the SIGLEC14 gene, the disease is at least one selected from the group consisting of contact dermatitis, knee osteoarthritis, prostate cancer, hearing loss, ureteral stones, kidney stones, and gastritis; for the single nucleotide polymorphism rs71353353 of the SIGLEC16 gene, the disease is at least one selected from the group consisting of congenital hip dislocation, ventricular fibrillation, autoimmune disease, pancreatitis, uterine cancer, and cerebral infarction (preferably congenital hip dislocation, ventricular fibrillation, and autoimmune disease, more preferably congenital hip dislocation); and for the single nucleotide polymorphism rs544574549 of the SIGLEC16 gene, the disease is at least one selected from the group consisting of systemic lupus erythematosus, bulimia nervosa, cerebral infarction, and macular degeneration (preferably systemic lupus erythematosus).

[0036] Disease risk can be tested by examining the presence or absence of the biomarkers of the present invention. From this viewpoint, in one aspect, the present invention provides: (1) a single nucleotide polymorphism in genomic DNA of a biological sample collected from a subject, the single nucleotide polymorphisms rs200137244 of the SIGLEC1 gene, rs143664589 of the SIGLEC1 gene, rs111336308 of the SIGLEC1 gene, rs3746636 of the SIGLEC1 gene, rs76943436 of the SIGLEC4 gene, rs11084810 of the SIGLEC4 gene, rs1807124 of the SIGLEC5 gene, rs2305773 of the SIGLEC6 gene, and rs111336308 of the SIGLEC1 gene. The present invention relates to a method for testing for disease risk, comprising a step of examining the presence or absence of at least one polymorphism selected from the group consisting of rs76001696, rs2305770, a single nucleotide polymorphism in the SIGLEC8 gene, rs7258951, a single nucleotide polymorphism in the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism in the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism in the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism in the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism in the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism in the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism in the SIGLEC16 gene. The present invention also relates to a method for detecting single nucleotide polymorphisms, comprising step (1). Herein, these methods are sometimes collectively referred to as the "methods of the present invention."

[0037] The biomarkers of the present invention are single nucleotide polymorphisms in human genes, and therefore the subject is a human.

[0038] Subjects whose disease risk can be predicted using the biomarkers of the present invention are not particularly limited, but are preferably Mongoloids, more specifically, individuals belonging to a population that shares genetic ancestry with the majority of residents in each country of East Asia (Japan, China, South Korea, North Korea, Taiwan, and Mongolia), or individuals equivalent thereto (note: for example, individuals residing in regions outside East Asia due to work or migration). Whether a subject belongs to such a population can be determined by genetic testing according to standard methods.

[0039] The number of subjects in a subject population to which the method of the present invention is applied is not particularly limited, and may be, for example, 10 or more, 50 or more, 100 or more, or 1000 or more. The upper limit of the number is not particularly limited, and may be, for example, 100,000, 10,000, or 5,000.

[0040] The condition of the subject is not particularly limited. Examples of the subject include a subject whose condition is unknown, a subject whose condition has already been determined by another method to be affected by the disease, a subject whose condition has already been determined by another method to be free of the disease, and a subject undergoing treatment for the disease. The testing method of the present invention can, for example, determine the disease status and risk of developing a disease in a subject whose condition is unknown, and test the risk of developing a disease in a subject who does not have the disease.

[0041] The biological sample is not particularly limited as long as it contains chromosomal genomic DNA contained in the nuclei of cells of a subject. Examples of biological samples include body fluids, skin, mucous membranes, and body tissues. Among these, body fluids, skin, and mucous membranes are preferred, and body fluids are more preferred, from the viewpoints of ease of collection and minimal invasiveness.

[0042] Examples of body fluids include blood, follicular fluid, menstrual blood, saliva, cerebrospinal fluid, synovial fluid, urine, tissue fluid, sweat, tears, etc. Examples of mucous membranes include oral mucosa, nasal mucosa, etc.

[0043] The biological sample may be one directly collected from a living organism, or may be a sample obtained by concentrating and purifying genomic DNA.

[0044] The biological sample may be used alone or in combination of two or more types.

[0045] Biological samples can be collected from subjects by methods known to those skilled in the art. For example, whole blood can be collected by drawing blood using a syringe or the like. It is desirable that blood be collected by a medical professional such as a doctor or nurse. Serum is a portion of blood from which blood cells and specific blood coagulation factors have been removed, and can be obtained, for example, as the supernatant after blood clotting. Plasma is a portion of blood from which blood cells have been removed, and can be obtained, for example, as the supernatant after centrifugation under conditions that do not cause blood clotting.

[0046] In step (1), the presence or absence of the biomarker of the present invention in the genomic DNA of a subject is examined. If the biomarker of the present invention is present, the subject can be determined to have a high risk of developing a disease or to have the disease, and if the biomarker of the present invention is absent, the subject can be determined to have a low risk of developing a disease or to be free of the disease.

[0047] The method for determining the presence or absence of a biomarker of the present invention is not particularly limited as long as it is a method capable of specifically detecting DNA of a particular base sequence, and various known methods or methods based on such methods can be employed. Examples of such methods include PCR (e.g., real-time PCR), DNA sequencing, DNA microarrays, Southern hybridization, etc. More specific examples include methods that use primers and probes specific to a polymorphism, amplify the PCR product, and detect the polymorphism in the PCR amplification product by luminescence; TaqMan-PCR, Invader PCR, methods using FRET, ASP-PCR, MALDI-TOF / MS using primer extension, RCA, methods using DNA chips or microarrays, and DigiTag2.

[0048] In one embodiment of the above method, DNA-binding molecules (e.g., primers, probes, etc.) can be used. Primer pairs and probes can be designed and synthesized based on the base sequences of the biomarkers of the present invention. The base lengths of the primers and probes are not particularly limited. The base length of a primer can be, for example, 10 to 50 nucleotides, preferably 15 to 30 nucleotides. The base length of a probe can be, for example, 10 to 5,000 nucleotides, preferably 10 to 1,000 nucleotides, more preferably 20 to 150 nucleotides.

[0049] The primer pair and probe may be made of natural nucleic acids such as RNA and DNA, or may be made of a combination of natural nucleic acids with chemically modified nucleic acids or pseudo nucleic acids, if necessary. Examples of chemically modified nucleic acids and pseudo nucleic acids include PNA (Peptide Nucleic Acid), LNA (Locked Nucleic Acid; registered trademark), methylphosphonate DNA, phosphorothioate DNA, and 2'-O-methyl RNA. Furthermore, the primer and probe may contain a fluorescent substance and / or a quencher substance, or a radioisotope (e.g., 32 P, 33 P, 35 The antibody may be labeled or modified with a labeling substance such as ATP (S), or a modifying substance such as biotin, (strept)avidin, or magnetic beads.

[0050] The labeling substance is not limited, and commercially available substances can be used. For example, fluorescent substances such as FITC, Texas, Cy3, Cy5, Cy7, Cyanine3, Cyanine5, Cyanine7, FAM, HEX, VIC, fluorescamine and its derivatives, and rhodamine and its derivatives can be used. Quencher substances such as AMRA, DABCYL, BHQ-1, BHQ-2, and BHQ-3 can be used. The labeling position of the labeling substance in the primer and probe can be determined appropriately depending on the properties of the modifying substance and the intended use. Generally, the 5' or 3' end is often modified. Furthermore, one primer and probe molecule may be labeled with one or more types of labeling substance. The design of the nucleotide sequences of primers and probes and the selection of labeling substances are well known and are disclosed in molecular biology experimental protocol books such as Molecular Cloning: A Laboratory Manual by Sambrook, J and Russell, DW (3rd ed., Cold Spring Harbor Laboratory Press, 2001).

[0051] Step (1) includes examining whether each single nucleotide polymorphism is present in both of the paired chromosomes, and examining whether each single nucleotide polymorphism is present in one of the paired chromosomes. Examples of single nucleotide polymorphisms include rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene, rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene, rs11084810, a single nucleotide polymorphism of the SIGLEC5 gene, rs1807124, a single nucleotide polymorphism of the SIGLEC6 gene, rs2305773, a single nucleotide polymorphism of the SIGLEC6 gene, rs76001696, a single nucleotide polymorphism of the SIGLEC8 gene, rs2305770, and S For rs145769059, a single nucleotide polymorphism in the IGLEC10 gene, rs74354979, a single nucleotide polymorphism in the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism in the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism in the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism in the SIGLEC16 gene, it is preferable to examine whether or not they are present in both of the paired chromosomes in order to determine the risk of developing a disease. On the other hand, it is predicted that the single nucleotide polymorphisms rs143664589 of the SIGLEC1 gene, rs111336308 of the SIGLEC1 gene, rs3746636 of the SIGLEC1 gene, rs7258951 of the SIGLEC10 gene, and rs200296439 of the SIGLEC11 gene are unlikely to be present in both of the paired chromosomes. Therefore, it is preferable to not only examine whether or not they are present in both of the paired chromosomes, but also whether or not they are present in one of the paired chromosomes, and from the viewpoint of test efficiency, it is more preferable to examine whether or not they are present in one of the paired chromosomes.

[0052] According to the method of the present invention including step (1), it is possible to provide information on the presence or absence of the biomarker of the present invention, which is an indicator for disease testing, and thereby to assist in assessing the risk of developing a disease, diagnosing a disease, etc.

[0053] The results of the method of the present invention including step (1) can be used to elucidate the pathology of a disease, predict the prognosis of a disease, stratify subjects / patients, select a treatment method (personalized medicine, treatment response), etc.

[0054] In one embodiment, the testing method of the present invention preferably further comprises: (2a) a step of determining that the subject has a high risk of developing a disease when at least one of the single nucleotide polymorphisms is detected in the step (1); and / or (2b) a step of determining that the subject has a low risk of developing a disease when at least one of the single nucleotide polymorphisms is not detected in the step (1).

[0055] In one aspect of the present invention, if rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of gastritis and allergic rhinitis, and if rs200137244 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0056] In one aspect of the present invention, if rs143664589, a single nucleotide polymorphism of the SIGLEC1 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of bulimia nervosa and multiple chemical sensitivity, and if rs143664589 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0057] In one aspect of the present invention, if rs111336308, a single nucleotide polymorphism of the SIGLEC1 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of anorexia nervosa, ulcerative colitis, bulimia nervosa, and mandibular protrusion, and if rs111336308 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0058] In one aspect of the present invention, if rs3746636, a single nucleotide polymorphism of the SIGLEC1 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of heart failure, hepatitis C, myocardial infarction, and angina pectoris, and if rs3746636 is not detected, the subject is determined to have a low risk of developing the disease.

[0059] In one aspect of the present invention, if rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of gallstones, gastric ulcers, hives, gastritis, and periodontal disease, and if rs76943436 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0060] In one aspect of the present invention, if rs11084810, a single nucleotide polymorphism of the SIGLEC4 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of heart failure, subarachnoid hemorrhage, gout, scoliosis, colorectal cancer, myocardial infarction, angina pectoris, and head trauma accompanied by loss of consciousness, and if rs11084810 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0061] In one aspect of the present invention, if rs1807124, a single nucleotide polymorphism of the SIGLEC5 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of endometriosis, allergic conjunctivitis, and iron deficiency anemia, and if rs1807124 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0062] In one aspect of the present invention, if rs2305773, a single nucleotide polymorphism of the SIGLEC6 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of chronic sinusitis, myocardial infarction, angina pectoris, and hearing loss, and if rs2305773 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0063] In one aspect of the present invention, if rs76001696, a single nucleotide polymorphism of the SIGLEC6 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of atopic dermatitis and hypertension, and if rs76001696 is not detected, the subject is determined to have a low risk of developing the disease.

[0064] In one aspect of the present invention, if rs2305770, a single nucleotide polymorphism of the SIGLEC8 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of iron deficiency anemia and myopia, and if rs2305770 is not detected, the subject is determined to have a low risk of developing the disease.

[0065] In one aspect of the present invention, if rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of collagen disease, ADHD, ventricular fibrillation, type 1 diabetes, fractures, ureteral stones, and kidney stones, and if rs7258951 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0066] In one aspect of the present invention, if rs145769059, a single nucleotide polymorphism in the SIGLEC10 gene, is detected in step (1), the subject is determined to have a high risk of developing migraine, and if rs145769059 is not detected, the subject is determined to have a low risk of developing the disease.

[0067] In one aspect of the present invention, if rs200296439, a single nucleotide polymorphism in the SIGLEC11 gene, is detected in step (1), the subject is determined to have a high risk of developing collagen disease, and if rs200296439 is not detected, the subject is determined to have a low risk of developing the disease.

[0068] In one aspect of the present invention, if rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of head trauma accompanied by loss of consciousness, chronic bronchitis, corneal disease, food allergy, hepatitis C, and migraine, and if rs74354979 is not detected, the subject is determined to have a low risk of developing the disease.

[0069] In one aspect of the present invention, if rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of contact dermatitis, osteoarthritis of the knee, prostate cancer, hearing loss, ureteral stones, kidney stones, and gastritis, and if rs111981406 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0070] In one aspect of the present invention, if rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of congenital hip dislocation, ventricular fibrillation, autoimmune disease, pancreatitis, uterine cancer, and cerebral infarction, and if rs71353353 is not detected, the subject is determined to have a low risk of developing the above-mentioned disease.

[0071] In one aspect of the present invention, if rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene, is detected in step (1), the subject is determined to have a high risk of developing at least one disease selected from the group consisting of systemic lupus erythematosus, bulimia nervosa, cerebral infarction, and macular degeneration, and if rs544574549 is not detected, the subject is determined to have a low risk of developing the disease.

[0072] The biomarker detector of the present invention can be used as a test agent for use in the method of the present invention. From this viewpoint, in one embodiment, the present invention provides a method for detecting a single nucleotide polymorphism of the SIGLEC1 gene, such as rs200137244, which is a single nucleotide polymorphism of the SIGLEC1 gene, rs143664589, which is a single nucleotide polymorphism of the SIGLEC1 gene, rs111336308, which is a single nucleotide polymorphism of the SIGLEC1 gene, rs3746636, which is a single nucleotide polymorphism of the SIGLEC1 gene, rs76943436, which is a single nucleotide polymorphism of the SIGLEC4 gene, rs11084810, which is a single nucleotide polymorphism of the SIGLEC5 gene, rs1807124, which is a single nucleotide polymorphism of the SIGLEC6 gene, rs2305773, which is a single nucleotide polymorphism of the SIGLEC6 gene, rs76001696, and rs11084810. The present invention relates to a test agent for use in the method of the present invention, comprising at least one detection agent selected from the group consisting of rs2305770, a single nucleotide polymorphism of the EC8 gene, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene. In this specification, these are sometimes collectively referred to as the "test agent of the present invention."

[0073] The detecting agent is not particularly limited as long as it can detect the biomarker of the present invention. Examples of the detecting agent include primers and probes for the biomarker of the present invention.

[0074] The detection agent may be modified as long as its function is not significantly impaired. Modifications include the addition of labels such as fluorescent dyes, enzymes, proteins, radioisotopes, chemiluminescent substances, biotin, etc.

[0075] Fluorescent dyes suitable for use in the present invention include those typically used to label nucleotides for the detection and quantification of nucleic acids. Examples include, but are not limited to, HEX (4,7,2',4',5',7'-hexachloro-6-carboxylfluorescein, a green fluorescent dye), fluorescein, NED (trade name, manufactured by Applied Biosystems, a yellow fluorescent dye), 6-FAM (trade name, manufactured by Applied Biosystems, a yellow-green fluorescent dye), and rhodamine or its derivatives (e.g., tetramethylrhodamine (TMR)). Nucleotides can be labeled with fluorescent dyes using any suitable known labeling method (see Nature Biotechnology, 14, 303-308 (1996)). Alternatively, commercially available fluorescent labeling kits (e.g., Oligonucleotide ECL 3'-Oligolabeling System, manufactured by Amersham-Pharmacia) can be used.

[0076] The detection agent can also be used by immobilizing it on any solid phase, and therefore the test agent of the present invention can be provided in the form of a substrate on which the detection agent is immobilized (for example, a microarray chip on which a probe is immobilized).

[0077] The solid phase used for immobilization is not particularly limited as long as it can immobilize polynucleotides, etc., and examples thereof include glass plates, nylon membranes, microbeads, silicon chips, capillaries, and other substrates. The immobilization of the detection agent to the solid phase is not particularly limited. For example, in the case of a microarray, a commercially available spotter (e.g., manufactured by Amersham) can be used. Immobilization methods are well known in the art depending on the type of immobilized probe (e.g., photolithographic technology (Affymetrix) or in situ synthesis of oligonucleotides using inkjet technology (Rosetta Inpharmatics)).

[0078] The primers, probes, etc. are not particularly limited as long as they selectively (specifically) recognize the biomarkers of the present invention. Here, "selectively (specifically) recognize" means, for example, that the biomarkers of the present invention are specifically amplified in the PCR method, but is not limited thereto, and may be any primers, probes, etc. that allow a person skilled in the art to determine the presence or absence of the biomarkers of the present invention based on the detected product, amplified product, or the presence or absence thereof.

[0079] Specific examples of primers and probes include at least one selected from the group consisting of the polynucleotides described in (a) below and the polynucleotides described in (b) below: (a) a polynucleotide having at least 15 consecutive bases in the base sequence of a gene having a biomarker of the present invention and / or a polynucleotide complementary to said polynucleotide, and (b) a polynucleotide having at least 15 bases that hybridizes under stringent conditions to the base sequence of a gene having a biomarker of the present invention or a base sequence complementary thereto.

[0080] A complementary polynucleotide or complementary base sequence (complementary strand, reverse strand) refers to a polynucleotide or base sequence that is base-complementary to the full-length polynucleotide sequence of a gene having a biomarker of the present invention, or a partial sequence thereof having at least 15 consecutive bases in length (herein referred to as the "positive strand" for convenience). However, such a complementary strand need not necessarily form a completely complementary sequence with the base sequence of the target positive strand, but may also have a complementary relationship to the target positive strand that allows hybridization under stringent conditions. The stringent conditions can be determined based on the melting temperature (Tm) of the nucleic acid to which the complex or probe binds, as taught by Berger and Kimmel (1987, Guide to Molecular Cloning Techniques Methods in Enzymology, Vol. 152, Academic Press, San Diego, CA). For example, typical post-hybridization washing conditions include approximately 1x SSC, 0.1% SDS, and 37°C. It is preferable that the complementary strand maintains its hybridization state with the target positive strand even when washed under these conditions. While not particularly limited, more stringent hybridization conditions include approximately 0.5x SSC, 0.1% SDS, and 42°C, and even more stringent hybridization conditions include approximately 0.1x SSC, 0.1% SDS, and 65°C. Specifically, examples of such complementary strands include a strand consisting of a nucleotide sequence that is completely complementary to the nucleotide sequence of the target positive strand, and a strand consisting of a nucleotide sequence that shares at least 90%, preferably 95%, more preferably 98% or more, and even more preferably 99% or more identity with the target positive strand.

[0081] Primers, probes, etc. can be designed, for example, based on the base sequence of the biomarker of the present invention, using, for example, various design programs.

[0082] The base length of a primer, probe, or the like is not particularly limited as long as it has a length of at least 15 consecutive bases as described above, and can be appropriately set depending on the application. For example, when used as a primer, the base length can be, for example, 15 to 35 bases, and when used as a probe, the base length can be, for example, 15 to 35 bases.

[0083] The test agent of the present invention may be in the form of a composition. The composition may contain other components as needed. Examples of other components include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, fragrances, chelating agents, etc.

[0084] The test agent of the present invention may be in the form of a kit. In addition to the detection agent or a composition containing the same, the kit may contain other materials that can be used to detect the biomarker of the present invention in genomic DNA of a biological sample from a subject. Specific examples of such materials include various reagents (e.g., buffer solutions), instruments (e.g., instruments for collecting, purifying, and separating biological samples), etc.

[0085] The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[0086] Test Example 1. Selection of SNPs in SIGLEC Family Genes 1 28 genetic polymorphisms with an allele frequency of 1% or higher that are particularly high or characteristic in Japanese people were extracted from the SIGLEC family genes extracted from the ToMMo Whole Genome Analysis Database (38KJPN). For details about the ToMMo Whole Genome Analysis Database, see, for example, papers listed at https: / / pubmed.ncbi.nlm.nih.gov / 37930845 / , https: / / pubmed.ncbi.nlm.nih.gov / 31240104 / , https: / / pubmed.ncbi.nlm.nih.gov / 30041597 / , etc.

[0087] From these 28 polymorphisms, we extracted the following: (1) Three polymorphisms (SIGLEC4 rs76943436, SIGLEC6 rs2305773, SIGLEC8 rs2305770) selected using an index (VarMeter) used to predict the severity of missense mutations among polymorphisms with an allele frequency 30 times higher than that of gnomAD; (2) Two polymorphisms with no homozygous individuals (AA group), contrary to the expected value (SIGLEC10 rs7258951 (expected value 3.3 individuals) and SIGLEC11 rs200296439 (expected value 10.4 individuals)); and (3) Two polymorphisms with significantly higher homozygous individuals (AA group), contrary to the expected value (SIGLEC16 rs71353353 (3 times) and SIGLEC16 rs544574549 (10 times)).

[0088] The selection method using VarMeter in (1) is as follows: For each polymorphism, the mutation energy and normalized solvent accessibility of the mutation site were calculated using the AlphaFold2 model and Discovery Studio.

[0089] The mutation energy (ΔΔGmut) was calculated using the AlphaFold2 model (Jumper et al. Nature 596, 583-589 (2021)) with the Calculate Mutation Energy / Stability module in Discovery Studio 2021 (BIOVIA, Dassault Systèmes, San Diego, CA, USA). 3D models of the variants were also generated using the Calculate Mutation Energy / Stability module in Discovery Studio 2021. The mutation energy ΔΔGmut corresponds to the difference in Gibbs free energy of folding between the wild-type and variant proteins (ΔΔGfolding), and is expressed by the following equation:

[0090] The solvent accessibility (SASA) is defined as the contact area with a water molecule, assuming a hard sphere with a radius of 1.4 Å. The folded state SASA was calculated using the AlphaFold model in Discovery Studio 2021. The denatured state SASA was based on literature values ​​(Oobatake M, Ooi T., Prog. Biophys. Mol. Biol., 59, 237-84, 1993). The normalized solvent accessibility is defined as follows:

[0091] Three polymorphisms (SIGLEC4 rs76943436, SIGLEC6 rs2305773, and SIGLEC8 rs2305770) were selected based on whether the mutation energy was 2 kcal / mol or more or the normalized solvent accessibility (normalized SASA) of the mutation site was 0.1 or less.

[0092] Similarly, for (2) and (3), the mutation energy and the normalized solvent accessibility of the mutation site were calculated.

[0093] Table 1 shows the calculation results of amino acid mutations, mutation energies, and normalized solvent accessibility of the mutation sites for the seven selected polymorphisms ((1) to (3)).

[0094]

[0095] Test Example 2. Selection of SNPs in SIGLEC Family Genes 2 Next, in addition to the variant extraction conditions in Test Example 1, we attempted to identify novel Siglec polymorphisms under the following conditions: (4) 96 polymorphisms with allele frequencies of 0.1% to 20% were extracted from the SIGLEC family genes extracted from the ToMMo whole genome analysis database (38KJPN). Of the 96 polymorphisms, the severity of 79 polymorphisms with allele frequencies more than 10 times higher than gnomAD V4 was evaluated using the VarMeter method described in 0067 to 0071. When a chi-square test was performed between three groups (RR, RA, and AA), seven polymorphisms (SIGLEC1 rs200137244, SIGLEC4 rs11084810, SIGLEC5 rs1807124, SIGLEC6 rs76001696, SIGLEC10 rs145769059, SIGLEC12 rs74354979, and SIGLEC14 rs111981406) with a p-value of P<0.05 were identified (Table 2).

[0096]

[0097] Test Example 3. Selection of SNPs in SIGLEC Family Genes 3 (5) 96 polymorphisms with allele frequencies between 0.1% and 20% were extracted from the SIGLEC family genes extracted from the ToMMo Whole Genome Analysis Database (38KJPN). From these 96 polymorphisms, the severity of polymorphisms with 0 homozygotes (Case AA = 0) and 2 or more heterozygotes (Case RA > 2) was assessed using VarMeter. A chi-square test was performed between two groups (RR and RA + AA), and three polymorphisms (SIGLEC1 rs143664589, rs111336308, rs3746636) with a p-value of P<0.05 were extracted (Table 3).

[0098]

[0099] Test Example 4. Calculation of Disease Risk Ratios Using SIGLEC gene information, disease risk ratios were calculated for each of the 17 polymorphisms (Tables 1, 2, and 3) selected in Test Examples 1, 2, and 3. Specifically, this was done as follows.

[0100] The SIGLEC gene information consists of five items: (a) disease name, (b) total number of samples, (c) number of affected and unaffected individuals in the reference homozygote group (RR group), heterozygote group (RA group), and polymorphism homozygote group (AA group), (d) p-value when a chi-squared test was performed on the presence or absence of disease (3 groups) x genotype (3 groups: RR, RA, AA), and (e) p-value when a chi-squared test was performed on the presence or absence of disease (2 groups) x genotype (2 groups: RR and RA + AA).

[0101] From the obtained data, the incidence risk ratio for each disease in the RA group and AA group compared with the RR group was calculated using the following formula X.

[0102] In addition, to narrow down the diseases correlated with SIGLEC gene variants, the selection and analysis conditions for the cohort data from ToMMo are as follows: (A) Data with significant differences in each SIGLEC gene, i.e., diseases with p<0.05 (significance level set at 5%). (B) Diseases where the incidence rate is twice as high as that of the RR group due to genetic polymorphisms, i.e., the risk ratio is ≥ 2. (C) Diseases where the number of affected individuals in the polymorphism homozygote group is ≥ 2. (D) Diseases where the incidence rate is 0.5 times as high as that of the RR group due to genetic polymorphisms, i.e., the risk ratio is ≥ 0.5.

[0103] Under these conditions, data that simultaneously satisfied conditions (A), (B), and (C), i.e., diseases for which the homozygous polymorphism group has an increased risk of developing, were extracted. Condition (C) was established to exclude cases in which the number of affected individuals in the homozygous polymorphism group was 0 or 1.

[0104] Regarding (C), the heterozygous polymorphism group (RA group) for SIGLEC10 rs7258951 and SIGLEC11 rs200296439 in Table 1 was 713 and 1268, respectively, and the expected occurrences of the homozygous polymorphism group (AA group) were 3.3 and 10.4, but the actual occurrences were 0. For SIGLEC1 rs143664589, rs111336308, and rs3746636 in Table 3, the RA group was 81, 106, and 132, respectively, and the expected occurrences of the homozygous polymorphism group (AA group) were 3.2, 7.4, and 14.5, but the actual occurrences were 0. Therefore, the incidence rates of these polymorphisms were calculated as a ratio to the heterozygous group.

[0105] The results are shown in Table 4. These polymorphisms have not been reported in the GWAS catalog.

[0106]

Claims

1. rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene; rs143664589, a single nucleotide polymorphism of the SIGLEC1 gene; rs111336308, a single nucleotide polymorphism of the SIGLEC1 gene; rs3746636, a single nucleotide polymorphism of the SIGLEC1 gene; rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene; rs11084810, a single nucleotide polymorphism of the SIGLEC5 gene; rs1807124, a single nucleotide polymorphism of the SIGLEC6 gene; rs2305773, a single nucleotide polymorphism of the SIGLEC6 gene; rs76001696, a single nucleotide polymorphism of the SIGLEC8 gene. a single nucleotide polymorphism of the SIGLEC10 gene; rs2305770, a single nucleotide polymorphism of the SIGLEC10 gene; rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene; rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene; rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene; rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene; rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene; rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene; and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

2. For rs200137244, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of gastritis and allergic rhinitis; for rs143664589, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of bulimia nervosa (binge eating) and multiple chemical sensitivity; for rs111336308, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of anorexia nervosa, ulcerative colitis, bulimia nervosa, and mandibular protrusion; and for rs3746636, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of heart failure, hepatitis C, myocardial infarction, and angina pectoris. For the single nucleotide polymorphism rs76943436 of the SIGLEC4 gene, the disease is at least one selected from the group consisting of gallstones, gastric ulcers, hives, gastritis, and periodontal disease; for the single nucleotide polymorphism rs11084810 of the SIGLEC4 gene, the disease is at least one selected from the group consisting of heart failure, subarachnoid hemorrhage, gout, scoliosis, colorectal cancer, myocardial infarction, angina pectoris, and head trauma accompanied by loss of consciousness; for the single nucleotide polymorphism rs1807124 of the SIGLEC5 gene, the disease is at least one selected from the group consisting of endometriosis, allergic conjunctivitis, and iron deficiency anemia; and for the single nucleotide polymorphism rs2305773 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of chronic sinusitis, myocardial infarction, angina pectoris, and hearing loss. For the single nucleotide polymorphism rs76001696 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of atopic dermatitis and hypertension; for the single nucleotide polymorphism rs2305770 of the SIGLEC8 gene, the disease is at least one selected from the group consisting of iron deficiency anemia and myopia; for the single nucleotide polymorphism rs7258951 of the SIGLEC10 gene, the disease is at least one selected from the group consisting of collagen disease, ADHD, ventricular fibrillation, type 1 diabetes, fractures, ureteral stones, and kidney stones; and for the single nucleotide polymorphism rs145769059 of the SIGLEC10 gene, the disease is migraine.For the single nucleotide polymorphism rs200296439 of the SIGLEC11 gene, the disease is a collagen disease; for the single nucleotide polymorphism rs74354979 of the SIGLEC12 gene, the disease is at least one selected from the group consisting of head trauma accompanied by loss of consciousness, chronic bronchitis, corneal disease, food allergy, hepatitis C, and migraine; for the single nucleotide polymorphism rs111981406 of the SIGLEC14 gene, the disease is at least one selected from the group consisting of contact dermatitis, knee osteoarthritis, prostate cancer, hearing loss, ureteral stones, kidney stones, and gastritis; and for the single nucleotide polymorphism rs71353353 of the SIGLEC16 gene, the disease is at least one selected from the group consisting of congenital hip dislocation, ventricular fibrillation, autoimmune disease, pancreatitis, uterine cancer, and cerebral infarction; The biomarker according to claim 1, wherein, for rs544574549, which is a single nucleotide polymorphism in the SIGLEC16 gene, the disease is at least one selected from the group consisting of systemic lupus erythematosus, bulimia nervosa, cerebral infarction, and macular degeneration.

3. (1) In the genomic DNA of the biological sample collected from the subject, the single nucleotide polymorphisms rs200137244 of the SIGLEC1 gene, rs143664589 of the SIGLEC1 gene, rs111336308 of the SIGLEC1 gene, rs3746636 of the SIGLEC1 gene, rs76943436 of the SIGLEC4 gene, rs11084810 of the SIGLEC5 gene, rs1807124 of the SIGLEC5 gene, rs2305773 of the SIGLEC6 gene, and rs760016 of the SIGLEC6 gene 96. A method for detecting a single nucleotide polymorphism, comprising the step of examining the presence or absence of at least one polymorphism selected from the group consisting of rs2305770, a single nucleotide polymorphism of the SIGLEC8 gene, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

4. (1) In the genomic DNA of the biological sample collected from the subject, the single nucleotide polymorphisms rs200137244 of the SIGLEC1 gene, rs143664589 of the SIGLEC1 gene, rs111336308 of the SIGLEC1 gene, rs3746636 of the SIGLEC1 gene, rs76943436 of the SIGLEC4 gene, rs11084810 of the SIGLEC5 gene, rs1807124 of the SIGLEC5 gene, rs2305773 of the SIGLEC6 gene, and rs7600169 of the SIGLEC6 gene 6. A method for testing the risk of developing a disease, comprising a step of examining the presence or absence of at least one polymorphism selected from the group consisting of rs2305770, a single nucleotide polymorphism of the SIGLEC8 gene, rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

5. The testing method according to claim 4, further comprising: (2a) a step of determining that the subject has a high risk of developing a disease if at least one of the single nucleotide polymorphisms is detected in the step (1); and / or (2b) a step of determining that the subject has a low risk of developing a disease if at least one of the single nucleotide polymorphisms is not detected in the step (1).

6. For rs200137244, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of gastritis and allergic rhinitis; for rs143664589, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of bulimia nervosa (binge eating) and multiple chemical sensitivity; for rs111336308, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of anorexia nervosa, ulcerative colitis, bulimia nervosa, and mandibular protrusion; and for rs3746636, a single nucleotide polymorphism in the SIGLEC1 gene, the disease is at least one selected from the group consisting of heart failure, hepatitis C, myocardial infarction, and angina pectoris. For the single nucleotide polymorphism rs76943436 of the SIGLEC4 gene, the disease is at least one selected from the group consisting of gallstones, gastric ulcers, hives, gastritis, and periodontal disease; for the single nucleotide polymorphism rs11084810 of the SIGLEC4 gene, the disease is at least one selected from the group consisting of heart failure, subarachnoid hemorrhage, gout, scoliosis, colorectal cancer, myocardial infarction, angina pectoris, and head trauma accompanied by loss of consciousness; for the single nucleotide polymorphism rs1807124 of the SIGLEC5 gene, the disease is at least one selected from the group consisting of endometriosis, allergic conjunctivitis, and iron deficiency anemia; and for the single nucleotide polymorphism rs2305773 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of chronic sinusitis, myocardial infarction, angina pectoris, and hearing loss. For the single nucleotide polymorphism rs76001696 of the SIGLEC6 gene, the disease is at least one selected from the group consisting of atopic dermatitis and hypertension; for the single nucleotide polymorphism rs2305770 of the SIGLEC8 gene, the disease is at least one selected from the group consisting of iron deficiency anemia and myopia; for the single nucleotide polymorphism rs7258951 of the SIGLEC10 gene, the disease is at least one selected from the group consisting of collagen disease, ADHD, ventricular fibrillation, type 1 diabetes, fractures, ureteral stones, and kidney stones; and for the single nucleotide polymorphism rs145769059 of the SIGLEC10 gene, the disease is migraine.For the single nucleotide polymorphism rs200296439 of the SIGLEC11 gene, the disease is a collagen disease; for the single nucleotide polymorphism rs74354979 of the SIGLEC12 gene, the disease is at least one selected from the group consisting of head trauma accompanied by loss of consciousness, chronic bronchitis, corneal disease, food allergy, hepatitis C, and migraine; for the single nucleotide polymorphism rs111981406 of the SIGLEC14 gene, the disease is at least one selected from the group consisting of contact dermatitis, knee osteoarthritis, prostate cancer, hearing loss, ureteral stones, kidney stones, and gastritis; and for the single nucleotide polymorphism rs71353353 of the SIGLEC16 gene, the disease is at least one selected from the group consisting of congenital hip dislocation, ventricular fibrillation, autoimmune disease, pancreatitis, uterine cancer, and cerebral infarction; The testing method according to claim 4, wherein for rs544574549, a single nucleotide polymorphism in the SIGLEC16 gene, the disease is at least one selected from the group consisting of systemic lupus erythematosus, bulimia nervosa, cerebral infarction, and macular degeneration.

7. rs200137244, a single nucleotide polymorphism of the SIGLEC1 gene; rs143664589, a single nucleotide polymorphism of the SIGLEC1 gene; rs111336308, a single nucleotide polymorphism of the SIGLEC1 gene; rs3746636, a single nucleotide polymorphism of the SIGLEC1 gene; rs76943436, a single nucleotide polymorphism of the SIGLEC4 gene; rs11084810, a single nucleotide polymorphism of the SIGLEC5 gene; rs2305773, a single nucleotide polymorphism of the SIGLEC6 gene; rs76001696, a single nucleotide polymorphism of the SIGLEC8 gene; and rs230577, a single nucleotide polymorphism of the SIGLEC8 gene.

8. A test agent for use in the detection method according to claim 3 and / or the test method according to any one of claims 4 to 7, comprising at least one detecting agent selected from the group consisting of rs7258951, a single nucleotide polymorphism of the SIGLEC10 gene, rs145769059, a single nucleotide polymorphism of the SIGLEC10 gene, rs200296439, a single nucleotide polymorphism of the SIGLEC11 gene, rs74354979, a single nucleotide polymorphism of the SIGLEC12 gene, rs111981406, a single nucleotide polymorphism of the SIGLEC14 gene, rs71353353, a single nucleotide polymorphism of the SIGLEC16 gene, and rs544574549, a single nucleotide polymorphism of the SIGLEC16 gene.

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