WO2010061697A1 - Gène sensible à une maladie de glaucome à pression normale, et utilisation de celui-ci - Google Patents

Gène sensible à une maladie de glaucome à pression normale, et utilisation de celui-ci Download PDF

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Publication number
WO2010061697A1
WO2010061697A1 PCT/JP2009/068098 JP2009068098W WO2010061697A1 WO 2010061697 A1 WO2010061697 A1 WO 2010061697A1 JP 2009068098 W JP2009068098 W JP 2009068098W WO 2010061697 A1 WO2010061697 A1 WO 2010061697A1
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human chromosome
region containing
region
single nucleotide
nucleotide polymorphism
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PCT/JP2009/068098
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Japanese (ja)
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信久 水木
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株式会社メニコン
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Priority to CN2009801472986A priority Critical patent/CN102224244A/zh
Publication of WO2010061697A1 publication Critical patent/WO2010061697A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91051—Acyltransferases other than aminoacyltransferases (general) (2.3.1)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/16—Ophthalmology
    • G01N2800/168—Glaucoma

Definitions

  • the present invention relates to a normal pressure glaucoma disease susceptibility gene and use thereof.
  • Glaucoma is a progressive refractory disease that causes damage to the optic nerve due to an increase in intraocular pressure that exceeds normal ocular pressure that can maintain normal visual function. If left untreated, the visual field stenosis may progress and cause blindness. Although it is currently the leading cause of blindness in Japan, the cause is unknown and accurate diagnosis and effective treatment are available. And there is no prevention.
  • normal-tension glaucoma NSG
  • NVG normal-tension glaucoma
  • NTG has a normal range of intraocular pressure, so it is difficult to detect by intraocular pressure test, and is often overlooked in health examinations and normal ophthalmic examinations. Since optic nerve damage does not recover, early detection and treatment are the most important in NTG. However, the progression is slow, and the central visual field is damaged late, so that subjective symptoms are poor, and the optic nerve injury progresses without the user's knowledge.
  • Non-patent Documents 1-15 Myocilin
  • optineurin Non-patent Documents 16-30
  • optic atrophy 1 Non-patent Documents 31-41
  • An object of the present invention is to find a normal-tension glaucoma disease susceptibility gene and provide a method for using the gene.
  • the gist of the present invention is as follows.
  • the polymorphic site in the region containing ELOVL5 of human chromosome 6 is a single nucleotide polymorphism international number rs222450, rs9474394, rs2816344, rs2816341, rs2518579, rs2518578, rs9367511, rs6915699, rs6930045, rs9370188, rs9382180, rs9382181, rs4486010, rs2816379, rs6939730, rs2817088, rs2817090, rs2816372, rs2562895, rs2816364, rs2562893, rs2817101, rs2816362, rs2816356, rs10948744, rs12183976, rs2562898, rs735860, rs715441, rs2057024, rs
  • rs2287929 and rs16896325 are selected from the group consisting of rs2287929 and rs16896325, and NCBI (v36.1) 65944399, Polymorphic sites in the region containing GLRX and / or C5orf27 of human chromosome 5 are single nucleotide polymorphism international numbers rs34896, rs34897, rs3777220, rs3777217, rs11738579, rs3777213, rs7736948, rs6556883, rs9314160, rs6876015, rs11135436, rs17085165, rs17085170 Rs10040697, rs6884979, rs7702848, rs2080947, rs10476660, rs154454, rs147295, rs17085249, rs11741590, rs37
  • Polymorphic sites in the region containing ANGPT1 of human chromosome 8 are single nucleotide polymorphism international numbers rs12549261, rs10955436, rs6981257, rs11774921, rs11781710, rs1954724, rs6997025, rs1892764, rs16875775, rs11778352, rs2584372, rs2246255, rs2022958, rs2022949, rs168759 Rs1010824, rs2507799, rs10505100, rs11777978, rs16875983, rs9297393, rs7009229, rs13257393, rs4077322, rs11997995, rs10505105, rs4133396, rs4133395, rs4341141, rs10505107, rs11780324, rs35
  • the polymorphic site in the region containing ELOVL5 of human chromosome 6 is a single nucleotide polymorphism international number rs2817088, rs2817090, rs2816372, rs2562895, rs2816364, rs2562893, rs2817101, rs2816362, rs2816356, rs2562898, rs735860, rs2057024, rs1570146, rs9463895, rs2235723, rs1346603, rs9474476, rs2294867, rs9349660, rs974323, rs6909592, rs9367520, rs9395854, rs209485, rs9395856, rs7747926, rs7738788, rs209500, rs9357760, rs9370196, rs2095
  • the polymorphic site in the region containing 11p11.2 of human chromosome 11 is a single nucleotide polymorphism international number rs11039112, rs747650, rs1685404, rs11570094, rs11039212, rs4992357, rs11605672, rs10742805, rs12419692, rs4752856, rs3817334, rs4752791, rs17788930, rs2305982, rs6485788, rs7924699 and rs1872167,
  • the polymorphic site in the region containing OR5R1 of human chromosome 11 is the single nucleotide polymorphism international number rs1586004, rs7940239, rs10791979, rs157
  • the polymorphic site in the region containing MAP6 and / or GDPD5 and / or SERPINH1 of human chromosome 11 consists of the single nucleotide polymorphism international numbers rs482458, rs661928, rs7128888, rs7129014, rs688727, rs12574551, rs17134231, rs12282340, rs10160335 and rs12281880 Selected from the group,
  • the polymorphic site in the region containing 11q23-24 of human chromosome 11 is selected from the group consisting of single nucleotide polymorphism international numbers rs664971, rs17120523 and rs528508
  • the polymorphic site in the region containing TAOK3 of human chromosome 12 is selected from the group consisting of single nucleotide polymorphism international numbers rs10850953, rs
  • a reagent for examining normal-tension glaucoma which comprises at least one component selected from the group consisting of the following components (a) and (b):
  • human number A probe capable of hybridizing to a region containing at least one polymorphic site in at least one region selected from the group consisting of a region containing CUX2 of chromosome 2 and a region containing TOM1L1 of human chromosome 17 ( 6)
  • a normal-tension glaucoma test kit comprising the reagent according to (5).
  • a host cell transformed with a vector containing the DNA sequence of the marker gene described in (7) is cultured, and a polypeptide encoded by the DNA sequence of the marker gene described in (7) is collected from the culture.
  • a method for producing a polypeptide is described in detail.
  • the present invention makes it possible to more accurately diagnose normal-tension glaucoma. Patients who have already developed a definitive diagnosis, and can be actively treated. In addition, since the risk rate for the onset is calculated for those who have not yet developed, it is recommended that the test be performed frequently for undeveloped patients with a high risk rate for the onset, leading to early detection.
  • region containing 6th chromosome and ELOVL5 and a healthy person is shown.
  • the horizontal axis shows the position of the gene in the region over 0.5 Mb, and the vertical axis shows the p-value, which is a significant difference index.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame.
  • SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • region containing a candidate gene is shown.
  • the horizontal axis indicates the positional relationship with the gene in the region in terms of Mb, and the vertical axis indicates the p value that is an index of significant difference.
  • the position and name of the gene are shown outside the lower frame. SNPs showing a significant difference between patients and healthy subjects in this region are present mainly in candidate genes, indicating that normal pressure glaucoma disease susceptibility genes are present in this region.
  • a gene related to normal-tension glaucoma is a region containing ELOVL5 of human chromosome 6, a region containing SRBD1 of human chromosome 2, and an ARPP of human chromosome 3.
  • human chromosome 4 EPHA5 region human chromosome 6 GMDS region
  • human chromosome 6p21.3 human chromosome 6 SYTL3 A region containing NXPH1 of human chromosome 7, a region containing LHFPL3 of human chromosome 7, a region containing GLB1L3 of human chromosome 11, a region containing ZNF407 of human chromosome 18, and PAX7 of human chromosome 1.
  • the present invention includes a region containing ELOVL5 of human chromosome 6, a region containing SRBD1 of human chromosome 2, a region containing ARPP-21 of human chromosome 3, a region containing EPHA5 of human chromosome 4, human chromosome 6
  • the region containing GMDS, the region containing 6p21.3 of human chromosome 6 (including HSPA1B), the region containing SYTL3 of human chromosome 6, the region containing NXPH1 of human chromosome 7, and the LHFPL3 of human chromosome 7 A region containing GLB1L3 of human chromosome 11, a region containing ZNF407 of human chromosome 18, a region containing PAX7 of human chromosome 1, a region containing PTPRF of human chromosome 1, 1q12- of human chromosome 1 region containing q21.1 (including CHD1L and / or FMO5), region containing 1q21.2-q21.3 of
  • a method for examining normal-tension glaucoma is provided.
  • the polymorphic site only needs to show a significant difference between a normal-tension glaucoma patient and a healthy person, and the p value that is an index of a significant difference between the normal-tension glaucoma patient and a healthy person is smaller. Things are desirable. For example, if the p-value is less than 0.05, it is customarily determined that it is clearly useful biologically. Includes the region containing ELOVL5 of human chromosome 6, the region containing SRBD1 of human chromosome 2, the region containing ARPP-21 of human chromosome 3, the region containing EPHA5 of human chromosome 4, and the GMDS of human chromosome 6.
  • a region containing 6p21.3 of human chromosome 6 (including HSPA1B), a region containing SYTL3 of human chromosome 6, a region containing NXPH1 of human chromosome 7, a region containing LHFPL3 of human chromosome 7, human Region containing GLB1L3 of chromosome 11, region containing ZNF407 of human chromosome 18, region containing PAX7 of human chromosome 1, region containing PTPRF of human chromosome 1, 1q12-q21.1 of human chromosome 1 ( Region containing CHD1L and / or FMO5), region containing 1q21.2-q21.3 of human chromosome 1 (including FDPS and / or ASH1L and / or KCNN3), FAM5B of human chromosome 1 and / or A region containing ASTN1, a region containing PKP1 of human chromosome 1, KLHL29 of human chromosome 2, and / or Is a region
  • the polymorphic site in the region containing ELOVL5 of human chromosome 6 includes single nucleotide polymorphism international numbers rs222450, rs9474394, rs2816344, rs2816341, rs2518579, rs2518578, rs9367511, rs6915699, rs6930045, rs9370188, rs9382180, rs9382181, rs4486010, rs2816379, rs6939730, rs2817088, rs2817090, rs2816372, rs2562895, rs2816364, rs2562893, rs2817101, rs2816362, rs2816356, rs10948744, rs12183976, rs2562898, rs735860, rs715441, rs2057024, rs1429
  • Polymorphic sites in the region containing SRBD1 of human chromosome 2 include single nucleotide polymorphism international numbers rs11686431, rs7580559, rs3908093, rs2343412, rs12623996, rs7573149, rs918810, rs6721199, rs7579209, rs10194925, rs17033378, rs2343466, rs17033398, rs6737172, rs4953226, rs3851333, rs12473388, rs11681887, rs35608719, rs11888802, rs11678872, rs2343468, rs13003019, rs6760244, rs12471726, rs2081297, rs10460504, rs7562458, rs4953230, rs4952763, rs
  • Polymorphic sites in the region containing ARPP-21 of human chromosome 3 include single nucleotide polymorphism international numbers rs1523048, rs1523029, rs12487524, rs1403468, rs872133, rs1523040, rs1523041, rs13069451, rs12629480, rs1357449, rs6801949, rs17033355, rs9873254, rs9839823, rs6794354, rs6794373, rs12637211, rs9855328, rs2037538, rs2037539, rs1523038, rs11718271, rs1608314, rs2197728, rs9311101, rs10490870, rs17033506, rs12634096, rs2359774, rs9860326, rs4678,
  • Polymorphic sites in the region containing EPHA5 of human chromosome 4 include single nucleotide polymorphism international numbers rs371925, rs4241661, rs170654, rs1514271, rs2063419, rs13102419, rs11131589, rs2167320, rs1159057, rs12501311, rs17086016, rs961489, rs7684130, rs3749526, rs4860651, rs11938753, rs1376417, rs10025570, rs1376416, rs2084682, rs7658065, rs9312144, rs1376412, rs17086181, rs17086185, rs6847413, rs2198103, rs12509018, rs17082122, rs6823779, rs1708
  • Polymorphic sites in the region containing 6p21.3 (including HSPA1B) of human chromosome 6 include single nucleotide polymorphism international numbers rs2248373, rs2248459, rs2248462, rs2248617, rs3749946, rs2523650, rs2904776, rs2516422, rs2905747, rs9267247, rs2395034 , Rs3095229, rs3131631, rs2516486, rs2734573, rs3115537, rs2516478, rs2071593, rs3219183, rs13215091, rs1799964, rs1052248, rs9348876, rs2857697, rs2736172, rs1046089, rs2255741, rs7603, rs844 Rs707974, rs805268, rs
  • Polymorphic sites in the region containing SYTL3 of human chromosome 6 include single nucleotide polymorphism international numbers rs602698, rs678116, rs649930, rs643677, rs592698, rs675053, rs612557, rs629364, rs627967, rs628203, rs2771425, rs9355655, rs10499309, rs1041566, rs12530454, rs7753885, rs9347236, rs6455585, rs6931414, rs10447366, rs9457403, rs9355246, rs4709219, rs4708797, rs4709226, rs4709235, rs6925091, rs3799195, rs6913912, rs894124, rs6903405, r
  • Polymorphic sites in the region containing NXPH1 of human chromosome 7 include single nucleotide polymorphism international numbers rs3807826, rs7802863, rs3757521, rs3757520, rs3807823, rs1861032, rs17145870, rs7805508, rs6977682, rs3807815, rs1008038, rs3807811, rs11769978, rs3779356, rs3807807, rs3807806, rs7455929, rs6463790, rs4620183, rs12668479, rs17147407, rs11762595, rs12702719, rs17147608, rs12154895, rs17403198, rs16873367, rs42949, rs2349188, rs6463805, rs78
  • polymorphic sites in the region containing LHFPL3 of human chromosome 7 include single nucleotide polymorphism international numbers rs41521, rs2188486, rs977641, rs17389507, rs10274138, rs17136882, rs13234807, rs7794181, rs7787988, rs7787976, rs17331134, rs1557689, rs6465984, rs7798273, rs2188494, rs1468143, rs10953427, rs2214087, rs4730006, rs6952170, rs17137313, rs4727599, rs17137382, rs10228106, rs42181, rs4730010, rs11763758, rs17137711, rs11763095, rs6977743, rs4520098, r
  • Polymorphic sites in the region containing GLB1L3 of human chromosome 11 include single nucleotide polymorphism international numbers rs11223704, rs470713, rs470935, rs641024, rs11606866, rs7131644, rs10894784, rs1031381, rs522134, rs4362160, rs473041, rs498602, rs554874, rs1144225, rs1595895, rs1146192, rs4936229, rs1144219, rs2510356, rs553231, rs512359, rs568044, rs10894798, rs10894799, rs11223765, rs10894800, rs7940114, rs10894801, rs10791357, rs3741100, rs3741098, rs
  • polymorphic sites in the region containing ZNF407 of human chromosome 18 include single nucleotide polymorphism international numbers rs3794941, rs17055278, rs514931, rs494721, rs17055426, rs2896769, rs12717033, rs7227977, rs10871527, rs10514139, rs17832851, rs17055756, rs1473224, rs2628125, rs8085262, rs8089151, rs2628123, rs4891199, rs17055919, rs10514148, rs17055185, rs2404482, rs10514149, rs4337381, rs2959165, rs12456768, rs4891217, rs9945585, rs9961644, rs9961742,
  • Polymorphic sites in the region containing PAX7 of human chromosome 1 include single nucleotide polymorphism international numbers rs3000058, rs2816030, rs16862061, rs2816040, rs2816046, rs4920334, rs4920516, rs4920335, rs2816064, rs6704504, rs1934057, rs2298893, rs2743208, rs2076021, rs2076020, rs2236826, rs2282704, rs2282699, rs624761, rs851123, rs2236817, rs685300, rs2056446, rs2841078, rs4920344, rs6669544, rs4076925, rs6603910, rs11261070, rs7539659, rs11261074,
  • Polymorphic sites in the region containing PTPRF of human chromosome 1 include single nucleotide polymorphism international numbers rs2494997, rs1999674, rs2842180, rs2255632, rs2251804, rs1334973, rs6687571, rs2039528, rs2819341, rs10890251, rs2367617, rs11210864, rs2782641, rs11210871, rs10890257, rs12058744, rs11210879, rs11210886, rs516790, rs641365, rs673485, rs643445, rs10789438, rs11210892, rs617899, rs660899, rs2274465, rs10789439, rs489319, rs607062, rs1078944
  • Polymorphic sites in the region containing 1q12-q21.1 (including CHD1L and / or FMO5) of human chromosome 1 include single nucleotide polymorphism international numbers rs2355388, rs6686200rs12122453, rs12122534, rs4950474, rs4950475, rs6593810, rs6657631, rs21327 , Rs517201, rs575115, rs2031481, rs2477568, rs2477569, rs692963, rs535827, rs4950361, rs6593732, rs17359526, rs6693631, rs11811023, rs4950371, rs2304893, rs6593739, rs7525703, rs2883434, rs3, 745 , Rs6703187, rs10793652, rs75
  • polymorphic sites in the region containing 1q21.2-q21.3 (including FDPS and / or ASH1L and / or KCNN3) of human chromosome 1 include single nucleotide polymorphism international numbers rs10752613, rs11583896, rs16835600, rs4434872, rs4567311 , Rs4363451, rs9427232, rs4845576, rs4520447, rs4845578, rs11585416, rs4845584, rs12033835, rs11581644, rs10908557, rs6701341, rs2297898, rs12048137, rs11264875, rs2066134, rs2494663, rs6671166, rs4845600, rs19853 Rs1212352, rs6672010, rs6702754, rs2274988,
  • Polymorphic sites in the region containing PKP1 of human chromosome 1 include single nucleotide polymorphism international numbers rs1122396, rs1722755, rs6413916, rs831771, rs1404401, rs831767, rs16847944, rs831765, rs16847947, rs831764, rs16847951, rs831762, rs8317553, rs16847994, rs831751, rs4915220, rs10157719, rs947379, rs12466, rs1592085, rs4915499, rs12134467, rs10158798, rs1954214, rs12046907, rs10920161, rs12117501, rs1997018, rs1880450, rs1857489, rs16848184, rs8683
  • Polymorphic sites in the region containing THRB of human chromosome 3 include single nucleotide polymorphism international numbers rs1397878, rs6765461, rs6801153, rs1464010, rs7630879, rs6550848, rs826375, rs1667765, rs826378, rs6808673, rs2519423, rs17194828, rs1562736, rs9310730, rs2683535, rs7652337, rs7652444, rs2683542, rs1667739, rs1505302, rs6799431, rs17014338, rs826249, rs10510540, rs6772213, rs851719, rs6792783, rs1354605, rs866651, rs958892, rs826225, r
  • Examples of the polymorphic site in the region containing MED12L and / or CLRN10S and / or GPR171 of human chromosome 3 include single nucleotide polymorphism international numbers rs13088412, rs9837084, rs744876, rs571170, rs358954, rs9833515, rs6440716, rs358967, rs1993404, rs9883677, rs2048229, rs16863149, rs891666, rs1835668, rs6787683, rs16863204, rs16863208, rs16863229, rs3732755, rs3773614, rs1231521, rs3108727, rs3773619, rs7649855, rs16863264, rs2870518, rs3846072, rs67813395, rs
  • the polymorphic site in the region containing SORBS2 of human chromosome 4 includes single nucleotide polymorphism international numbers rs10866277, rs12645545, rs12649063, rs7437897, rs11132327, rs10866278, rs6823490, rs6843640, rs6818789, rs2512307, rs6552895, rs6552896, rs6552897, rs12498673, rs10025265, rs2306707, rs3749579, rs6848934, rs2306703, rs11934819, rs4862558, rs4599460, rs4862559, rs6823546, rs11132334, rs5018568, rs904451, rs7677363, rs2030144, rs11132338,
  • Polymorphic sites in the region containing GLRX and / or C5orf27 of human chromosome 5 include single nucleotide polymorphism international numbers rs34896, rs34897, rs3777220, rs3777217, rs11738579, rs3777213, rs7736948, rs6556883, rs9314160, rs6876015, rs11135436, rs17085165, rs17085170, rs10040697, rs6884979, rs7702848, rs2080947, rs10476660, rs154454, rs147295, rs17085249, rs11741590, rs3777194, rs2270554, rs3777190, rs3777188 and rs4642392, NCBI (v36.1) 95206085, etc. None happen.
  • Polymorphic sites in the region containing EBF1 of human chromosome 5 include single nucleotide polymorphism international numbers rs2913384, rs173423, rs244654, rs824854, rs824848, rs1095103, rs403334, rs10515769, rs2112262, rs33196, rs17056089, rs2042875, rs3843489, rs1541649, rs17056186, rs2116727, rs10067813, rs7709065, rs17056205, rs1368298, rs4704963, rs10070743, rs4704967, rs10056564, rs6875710, rs17643057, rs6883655, rs891903, rs10054046, rs6556373, rs4921538, 655 Examples include
  • Polymorphic sites in the region containing 6p21.31-p21.3 (including HLA-DPA1) of human chromosome 6 include single nucleotide polymorphism international numbers rs1044043, rs10484565, rs241438, rs1800454, rs241429, rs241427, rs4711312, rs2071482 , Rs4148882, rs12529313, rs9276815, rs92547, rs9276825, rs9276832, rs241404, rs241403, rs3101942, rs241400, rs3132132, rs151719, rs1050391, rs9378127, rs188245, rs3129305, rs176248, rs12216336, rs2894311, rs12191230, 1922391, , Rs399604, rs365066,
  • Polymorphic sites in the region including LOC100132919 of human chromosome 6 include single nucleotide polymorphism international numbers rs1338657, rs9485685, rs9377361, rs9377365, rs9377366, rs9322660, rs9322661, rs2399802, rs17063309, rs680011, rs9499111, rs9404214, rs1569366, rs1569367, Examples thereof include, but are not limited to, rs17443301, rs17063399, rs6906578 and rs7740643, NCBI (v36.1) 102984444, and the like.
  • polymorphic sites in the region containing AAA1 and / or NPSR1 of human chromosome 7 include the single nucleotide polymorphism international numbers rs1156490, rs6462540, rs1419842, rs2392267, rs1419803, rs1419805, rs1419809, rs6977125, rs17169769, rs17169771, rs7778512, rs1419840, rs35114106, rs1019089, rs16878925, rs1362172, rs2392270, rs17831435, rs10951417, rs1468559, rs10486643, rs6951496, rs7458608, rs2893480, rs4723375, rs1419863, rs1419864, rs9639694, rs9639695, 1737, rs
  • the polymorphic sites in the region containing ELMO1 of human chromosome 7 include single nucleotide polymorphism international numbers rs10277512, rs4720221, rs7787226, rs10951500, rs10274668, rs10255208, rs2006882, rs2392472, rs756507, rs2241152, rs7785934, rs7782979, rs17170754, rs3807162, rs3734948, rs741302, rs2041801, rs2049661, rs669276, rs4723592, rs11769038, rs4723598, rs1882080, rs4723601, rs11982286, rs1986619, rs1882082, rs10268319, rs17170799, rs6957979, rs10225164, r
  • the polymorphic sites in the region containing ANGPT1 of human chromosome 8 include single nucleotide polymorphism international numbers rs12549261, rs10955436, rs6981257, rs11774921, rs11781710, rs1954724, rs6997025, rs1892764, rs16875775, rs11778352, rs2584372, rs2246255, rs2022958, rs2022949, rs16875901, rs1010824, rs2507799, rs10505100, rs11777978, rs16875983, rs9297393, rs7009229, rs13257393, rs4077322, rs11997995, rs10505105, rs4133396, rs4133395, rs4341141, rs10505107, rs11780324,
  • polymorphic sites in the region containing PGM5 of human chromosome 9 include single nucleotide polymorphism international numbers rs3869296, rs7020465, rs11142449, rs11142461, rs10868851, rs13439981, rs7039076, rs265083, rs2131355, rs265087, rs265073, rs7861495, rs10869020, rs17085775, Examples thereof include, but are not limited to, rs11795256, rs10869034, rs1411992, rs10869043, rs12343877, rs11142941, rs869950, rs7046236, rs9644996, and the like.
  • Polymorphic sites in the region containing TMC1 of human chromosome 9 include single nucleotide polymorphism international numbers rs3012514, rs7846808, rs7027640, rs10781101, rs4526421, rs7853275, rs10869178, rs7864535, rs12004208, rs6560277, rs4573342, rs4132905, rs4073227, rs10121866, rs7044241, rs7855743, rs4373587, rs11143314, rs7047875, rs6560284, rs6560285, rs7857300, rs6560287, rs7866185, rs6560293, rs7026124, rs12346185, rs7041300, rs4307407, rs17095, rs10113863,
  • Polymorphic sites in the region containing ROR2 of human chromosome 9 include single nucleotide polymorphism international numbers rs6479357, rs9409602, rs10991978, rs10991988, rs7867934, rs1388966, rs902923, rs902922, rs10512215, rs1532230, rs12337820, rs7029450, rs2131304, rs2920304, rs9299395, rs1388967, rs4073736, rs4073735, rs9409652, rs10992075, rs7031729, rs17585790, rs16907725, rs16907728, rs4372069, rs16907761, rs16907764, rs17586213, rs7039620, rs16907768, r
  • Polymorphic sites in the region containing PPP6C and / or C9orf126 of human chromosome 9 include single nucleotide polymorphism international numbers rs7022663, rs7024526, rs2289631, rs10986505, rs16927802, rs12001999, rs10819019, rs6478690, rs1017530, rs3824507, rs12352758, rs4838242, rs650599, rs7860360, rs2113352, rs7019234, rs7867749, rs2271746, rs16927930, rs10986618, rs10986626, rs12237026, rs463774, rs420423, rs10986641, rs10513445, rs393721, rs10819043, rs10986689, rs
  • polymorphic sites in the region containing 11p11.2 of human chromosome 11 include single nucleotide polymorphism international numbers rs7124648, rs7128650, rs4587689 , Rs11039097, rs12796744, rs17197619, rs17790390, rs11039105, rs10501319, rs11039112, rs747650, rs7937410, rs17197710, rs1685404, rs2013867, rs901746, rs7118396, rs10838681, rs10501321, rs1051006, rs3816724, rs7124955, rs47510, rs7124955, rs47510 Rs11605672, rs153
  • the polymorphic sites in the region containing OR5R1 of human chromosome 11 include single nucleotide polymorphism international numbers rs1586004, rs7940239, rs10896302, rs17615246, rs10750820, rs1945245, rs3938998, rs10791979, rs1573511, rs12277883, rs7116573, rs10896333, rs4420287, rs1894026, rs1945213, rs1945211, rs7113069, rs11228306, rs12785840, rs10501353, rs1945203, rs585475, rs615231, rs617315, rs675991, rs7939886, rs4939052, rs621957, rs611534, rs594854, rs618594,
  • polymorphic sites in the region containing MAP6 and / or GDPD5 and / or SERPINH1 of human chromosome 11 include single nucleotide polymorphism international numbers rs565976, rs534179, rs2276443, rs532454, rs511190, rs566818, rs482458, rs1793412, rs1790149, rs1790155, rs1790154, rs668727, rs11600640, rs611449, rs11236449, rs661928, rs621305, rs11236452, rs7128888, rs7129014, rs688727, rs674503, rs606452, rs11236458, rs599816, rs660343, rs541993, rs601142, rs648930, rs61
  • polymorphic sites in the region containing 11q23-24 (including PCSK7 and / or RNF214) of human chromosome 11 include single nucleotide polymorphism international numbers rs17120344, rs6589597, rs10790175, rs12420127, rs10892082, rs7107152, rs1242229, rs1784042, rs2269399 , Rs526602, rs664971, rs11216315, rs1263499, rs17120523, rs236919, rs528508, rs593245 and rs477036, NCBI (v36.1) 116617736, and the like, but are not limited thereto.
  • Polymorphic sites in the region containing TAOK3 of human chromosome 12 include single nucleotide polymorphism international numbers rs7297299, rs5745807, rs5745811, rs9739560, rs4767654, rs10638, rs9788041, rs11068799, rs11068803, rs10850953, rs7135008, rs11613924, rs7307331, rs9667334, rs7957463, rs10850956, rs2936840, rs904661, rs1726407, rs1726392, rs17440336, rs1277442, rs11068860, rs11068865, rs17512142, rs17440364, rs364823, rs418941, rs7974718, rs11068891, rs16948230,
  • polymorphic sites in the region including CARS2 of human chromosome 13 include single nucleotide polymorphism international numbers rs9521809, rs4773201, rs1106649, rs9521814, rs385037, rs7997619, rs912941, s1886871, rs2182271, rs912942, rs331596, rs9559844, rs331602, rs1536621, rs9521853, rs9559849, rs7999854, rs3858821, rs4771696, rs4773228, rs4773229, rs2765341, rs3742193, rs3742194, rs7323602, rs3759463, rs179356, rs330565, rs7394, rs389656, rs450514, rs445490
  • Polymorphic sites in the region containing CYP19A1 of human chromosome 15 include single nucleotide polymorphism international numbers rs6493469, rs12595526, rs8031702, rs17599974, rs16953045, rs10744956, rs2306335, rs6493470, rs7181201, rs11856609, rs1124769, rs17647040, rs12899586, rs12904155, rs7170455, rs7177664, rs8040954, rs17647084, rs4775916, rs1111266, rs16964077, rs1025738, rs7179084, rs7176579, rs16964113, rs10519293, rs17522553, rs12324478, rs1075681, rs2899469, rs
  • Polymorphic sites in the region containing LOC643542 of human chromosome 18 include single nucleotide polymorphism international numbers rs8086948, rs12457951, rs11151371, rs17077389, rs1480679, rs5000099, rs1480682, rs433411, rs370944, rs395074, rs379982, rs281571, rs1444106, rs2448716, rs1562072, rs1867412, rs17077583, rs764133, rs17828615, rs2440515, rs10503119, rs2318439, rs12607172, rs9319737, rs1444112, rs2448755, rs2448745, rs2440527, rs28379561, rs10503118, rs1562070,
  • polymorphic sites in the region containing PTPRT of human chromosome 20 include single nucleotide polymorphism international numbers rs1884029, rs6072606, rs2207220, rs4812571, rs4572656, rs2013923, rs4812574, rs6513762, rs6513763, rs6029950, rs2144009, rs2866941, rs6102658, rs2144011, rs3787282, rs746413, rs4812578, rs6102671, rs1126101, rs6065434, rs4810352, rs1076666, rs6029980, rs6016688, rs2076249, rs17221018, rs17221067, rs17312515, rs17221137, rs6130047, rs16986551, rs
  • Polymorphic sites in the region containing ITSN1 of human chromosome 21 include single nucleotide polymorphism international numbers rs12626309, rs2834231, rs4817579, rs2834238, rs2211689, rs2834246, rs2834251, rs2834252, rs1537097, rs1892589, rs2073368, rs2409499, rs9978415, rs2268247, rs9979937, rs2834264, rs2834268, rs8794268, rs879261, rs2245099, rs1108000, rs9979150, rs743316, rs2300384, rs3746861, rs2834292, rs2834295, rs2040113, rs2834296, rs2834297, rs2239565,
  • Polymorphic sites in the region containing LRP2 of human chromosome 2 include single nucleotide polymorphism international numbers rs13416802, rs2287616, rs2287613, rs3770597, rs10200158, rs6761690, rs13430236, rs3814381, rs4148765, rs10490134, rs11902639, rs10183805, rs13403114, rs3815574, rs2302698, rs6750251, rs4667590, rs4668121, rs1990702, rs6746604, rs990627, rs990626, rs2268380, rs6733122, rs2284681, rs11679947, rs10490132, rs2239602, rs2024481, rs741378, rs2284679
  • Polymorphic sites in the region containing APIP and / or PDHX of human chromosome 11 include single nucleotide polymorphism international numbers rs523246, rs10501136, rs836950, rs12808574, rs10836315, rs502857, rs731726, rs731727, rs967751, rs1553760, rs1396880, rs2941043, rs2941042, rs2941061, rs2956079, rs2941054, rs1509662, rs2941052, rs2915234, rs891550, rs919554, rs2915232, rs2956086, rs1998603, rs2985390, rs1571134, rs1571135, rs2915224, rs1430855, rs3751078, 291513,
  • Polymorphic sites in the region containing CUX2 of human chromosome 12 include single nucleotide polymorphism international numbers rs7979656, rs10849918, rs2106407, rs2106406, rs12425190, rs11065783, rs2339706, rs4509829, rs7961663, rs4766526, rs4766442, rs4766443, rs12815195, rs12229654, rs756825, rs16941284, rs6489979, rs4766553, rs9783423, rs7952972, rs16941319, rs3809290, rs7962233, rs4766451, rs886126, rs2078851, rs1265566, rs2301658, rs7300082, rs7300860, rs16941414,
  • Polymorphic sites in the region containing TOM1L1 of human chromosome 17 include single nucleotide polymorphism international numbers rs2332297, rs2934884, rs16955216, rs2934890, rs7225247, rs16955225, rs9303359, rs7207731, rs17683089, rs11658131, rs2958944, rs2934909, rs2934914, rs2934921, rs2958933, rs7221313, rs7210248, rs2958921, rs8079105, rs16955327, rs12949718, rs9899602, rs17745123, rs8070668, rs9910653, rs17817829, rs12936860, rs12951898, rs17817950, rs2787501, NC
  • SNP single nucleotide polymorphism
  • normal tension glaucoma examination is an examination for determining whether or not a subject has a high or low possibility of having normal tension glaucoma. Tests to make a definitive diagnosis are included.
  • polymorphic site in the test method of the present invention refers to a gene ORF, a region that controls gene expression (for example, a promoter region, an enhancer region, etc.), a gene intron, or a linkage disequilibrium with these genes. It can exist in the area before and after that.
  • polymorphisms include single nucleotide polymorphisms, polymorphisms in which one to several tens of bases (sometimes several thousand bases) are substituted, deleted, inserted, transferred, or inverted. There is no particular limitation. Further, the number of polymorphic sites is not limited to one and may be plural.
  • identification of the base at the polymorphic site can be performed by the following method.
  • a method of comparing the intensity of hybridization using a probe specific for the polymorphic part A method for identifying a base incorporated into a polymorphic site during a polymerase base extension reaction initiated from a template-specific primer in the polymorphic region.
  • ⁇ Base-pair or non-complementary complementary to polymorphic region following template-specific primer To make the enzyme recognize the presence or absence of basic base pairs. The above are typical SNP detection methods, but the normal-tension glaucoma examination of the present invention is not limited to these methods.
  • genomic DNA may be extracted from the subject's biological sample.
  • biological samples include, for example, the subject's blood, skin, oral mucosa, tissues or cells collected or excised by surgery, body fluids collected for the purpose of examination (saliva, lymph, airway mucosa, semen, sweat, urine, etc.) ) Etc.
  • As the biological sample leukocytes or mononuclear cells separated from peripheral blood are preferable.
  • Genomic DNA can be extracted from a biological sample using a commercially available DNA extraction kit. Then, if necessary, DNA containing the polymorphic site is isolated. The DNA can be isolated by PCR or the like using genomic DNA or RNA as a template, using a primer capable of hybridizing to DNA containing a polymorphic site.
  • the present invention also provides a reagent for examining normal-tension glaucoma, which comprises at least one component selected from the group consisting of the following components (a) and (b): .
  • Polymorphic site in human chromosome 6 containing ELOVL5, polymorphic site in human chromosome 2 containing SRBD1, polymorphic site in human chromosome 3 containing ARPP-21, human chromosome 4 EPHA5 The polymorphic site in the region containing GMDS, the polymorphic site in the region containing GMDS of human chromosome 6, the polymorphic site in the region containing 6p21.3 of human chromosome 6 (including HSPA1B), and SYTL3 of human chromosome 6
  • the present invention provides a test kit for normal-tension glaucoma containing the above reagent.
  • the above primers and probes may be oligonucleotides having a chain length of at least 15 nucleotides.
  • the oligonucleotide When the oligonucleotide is used as a primer, its length is usually 15 to 100 bp, preferably 17 to 30 bp.
  • the primer is not particularly limited as long as it can amplify at least a part of the DNA containing the polymorphic site.
  • the length of DNA that can be amplified by the primer is usually 15 to 1000 bp, preferably 20 to 500 bp, more preferably 20 to 200 bp.
  • the oligonucleotide When the oligonucleotide is used as a probe, the length is usually 15 bp to 500 bp, preferably 30 bp to 500 bp.
  • the probe is not particularly limited as long as it can hybridize with the DNA containing the polymorphic site.
  • the length of DNA to which the probe can hybridize is usually 16 to 500
  • a primer capable of amplifying a region containing a polymorphic site is preferably one that can initiate complementary strand synthesis toward the polymorphic site using a DNA containing the polymorphic site as a template.
  • an arbitrary base sequence can be added to the primer.
  • a primer for a polymorphism analysis method using a type IIs restriction enzyme a primer to which a recognition sequence for a type IIs restriction enzyme is added is used.
  • the primer may be modified.
  • a primer labeled with a fluorescent substance or a binding affinity substance such as biotin or digoxin may be used.
  • the probe that can hybridize to the region containing the polymorphic site may be any probe that can hybridize to the polynucleotide having the base sequence of the region containing the polymorphic site.
  • Those that specifically hybridize to DNA having the base sequence of the region to be included are preferred.
  • “specifically hybridizes” means normal hybridization conditions, preferably stringent hybridization conditions (for example, Sambrook et al., Molecular® Cloning, Cold® Spring® Harbor® Laboratory® Press, New® York, USA, In the condition described in the second edition 1989), it means that cross-hybridization does not occur significantly with DNA other than DNA having the base sequence of the region containing the polymorphic site.
  • a probe containing a polymorphic site in the base sequence of the probe is preferable.
  • the probe may be designed so that the end of the probe corresponds to a base adjacent to the polymorphic site. Therefore, although the polymorphic site is not included in the base sequence of the probe itself, a probe including a base sequence complementary to the region adjacent to the polymorphic site can also be shown as a desirable probe in the present invention.
  • the probe is allowed to modify the base sequence, add the base sequence, or modify the base sequence in the same manner as the primer.
  • a probe used for the Invader method is added with a base sequence unrelated to the genome constituting the flap.
  • Such a probe is also included in the probe of the present invention as long as it hybridizes to a region containing a polymorphic site.
  • the base sequence constituting the probe of the present invention can be designed according to the analysis method based on the base sequence of the DNA region surrounding the polymorphic site of the present invention in the genome.
  • primers and probes can be designed according to the analysis method based on the base sequence information about the surrounding DNA region including the polymorphic site.
  • the base sequences constituting the primers and probes can be modified as appropriate as well as the base sequences that are completely complementary to the genomic base sequences.
  • Primers and probes can be synthesized by any method based on the base sequences constituting them.
  • a technique for synthesizing an oligonucleotide having the base sequence based on the given base sequence is known.
  • any modification can be introduced into the oligonucleotide using a nucleotide derivative modified with a fluorescent dye or biotin.
  • a method of binding a fluorescent dye or the like to a synthesized oligonucleotide is also known.
  • the probe may be fixed on a solid phase (DNA array).
  • sample DNA or RNA
  • RNA is hybridized to a large number of probes arranged on the same plane, and the hybridization to each probe is detected by scanning the plane. Since responses to many probes can be observed simultaneously, for example, a DNA array is useful for analyzing a large number of polymorphic sites simultaneously.
  • nucleotide immobilization (array) methods include arrays based on oligonucleotides developed by Affymetrix. In an array of oligonucleotides, the oligonucleotides are usually synthesized in situ. For example, in-situ synthesis methods of oligonucleotides by lithography method (Affymetrix), inkjet method (Agilent), bead array method (Illumina), etc. are known.
  • Oligonucleotide is composed of a base sequence complementary to a region containing a polymorphic site to be detected.
  • the length of the nucleotide probe to be bound to the substrate is usually 10 to 100 bp, preferably 10 to 50 bp, more preferably 15 to 25 bp when the oligonucleotide is immobilized.
  • a sample for SNP detection by the DNA array method can be prepared by a method well known to those skilled in the art based on a biological sample collected from a subject.
  • the biological sample is not particularly limited.
  • a DNA sample can be prepared from genomic DNA extracted from tissues or cells of peripheral blood leukocytes, skin, oral mucosa, etc., tears, saliva, urine, feces or hair of the subject.
  • a specific region of genomic DNA is amplified using a primer for amplifying a region containing a polymorphic site to be determined.
  • a plurality of regions can be simultaneously amplified by the multiplex PCR method.
  • the multiplex PCR method is a PCR method using a plurality of primer sets in the same reaction solution. When analyzing multiple polymorphic sites, the multiplex PCR method is useful.
  • a DNA sample is amplified by the PCR method and the amplified product is labeled.
  • a labeled primer is used for labeling the amplification product.
  • genomic DNA is first amplified by PCR using a primer set specific to the region containing the polymorphic site.
  • biotin-labeled DNA is synthesized by a labeling PCR method using a biotin-labeled primer.
  • the biotin-labeled DNA synthesized in this way is hybridized to the oligonucleotide probe on the chip.
  • the hybridization reaction solution and reaction conditions can be appropriately adjusted according to conditions such as the length of the nucleotide probe immobilized on the solid phase and the reaction temperature.
  • One skilled in the art can design appropriate hybridization conditions.
  • avidin labeled with a fluorescent dye is added.
  • the array is analyzed with a scanner, and the presence or absence of hybridization is confirmed using fluorescence as an index.
  • An example of a procedure for carrying out the test method of the present invention using the DNA array method is as follows. After preparing a solid phase on which a DNA and nucleotide probe containing a polymorphic site prepared from a subject are immobilized, The solid phase is contacted. Subsequently, the base species of the polymorphic site is determined by detecting DNA hybridized to the nucleotide probe immobilized on the solid phase.
  • solid phase means a material capable of immobilizing nucleotides.
  • the solid phase is not particularly limited as long as nucleotides can be immobilized, and specific examples include a solid phase containing microplate wells, plastic beads, magnetic particles, a substrate, and the like.
  • a substrate generally used in DNA array technology can be preferably used.
  • the “substrate” means a plate-like material capable of fixing nucleotides.
  • the nucleotide includes oligonucleotides and polynucleotides.
  • an allele-specific oligonucleotide (Aligonucleotide / ASO) hybridization method can be used to detect a base at a specific site.
  • An allele-specific oligonucleotide (ASO) is composed of a base sequence that hybridizes to a region where a polymorphic site to be detected exists.
  • ASO is hybridized to sample DNA, the hybridization efficiency decreases if a mismatch occurs at the polymorphic site due to the polymorphism.
  • Mismatches can be detected by Southern blotting or a method that uses the property of quenching by intercalating a special fluorescent reagent into the hybrid gap. Mismatches can also be detected by the ribonuclease A mismatch cleavage method.
  • the reagents and kits of the present invention can contain various enzymes, enzyme substrates, buffers, and the like depending on the base identification method.
  • the enzyme include enzymes necessary for the various analysis methods exemplified as the base identification method, such as DNA polymerase, DNA ligase, or IIs restriction enzyme.
  • the buffer solution a buffer solution suitable for maintaining the activity of the enzyme used for these analyzes is appropriately selected.
  • the enzyme substrate for example, a substrate for complementary strand synthesis is used.
  • a control in which the base at the polymorphic site is clear can be attached to the reagent and kit of the present invention.
  • genomic DNA or a fragment of genomic DNA in which the base type of the polymorphic site is known in advance can be used.
  • Genomic DNA extracted from cells may be attached as a control, or a cell or a fraction of cells may be attached as a control, and a user may extract genomic DNA therefrom. If a cell is used as a control, the result of the control can prove that the genomic DNA extraction operation was performed correctly.
  • DNA comprising a base sequence containing a polymorphic site can be used as a control.
  • a YAC vector or a BAC vector containing a genome-derived DNA whose base type at the polymorphic site has been clarified may be used as a control.
  • a vector in which only tens to hundreds of bp corresponding to the polymorphic site are excised and inserted can be used as a control.
  • the present invention also includes a region containing ELOVL5 of human chromosome 6, a region containing SRBD1 of human chromosome 2, a region containing ARPP-21 of human chromosome 3, a region containing EPHA5 of human chromosome 4, The region containing 6 chromosomes of GMDS, the region containing human chromosome 6p21.3 (including HSPA1B), the region containing human chromosome 6 SYTL3, the region containing human chromosome 7 NXPH1, the region of human chromosome 7 A region containing LHFPL3, a region containing GLB1L3 of human chromosome 11, a region containing ZNF407 of human chromosome 18, a region containing PAX7 of human chromosome 1, a region containing PTPRF of human chromosome 1, Region containing 1q12-q21.1 (including CHD1L and / or FMO5), region containing 1q21.2-q21.3 (including FDPS and /
  • Polymorphic site in human chromosome 6 containing ELOVL5, polymorphic site in human chromosome 2 containing SRBD1, polymorphic site in human chromosome 3 containing ARPP-21, human chromosome 4 EPHA5 The polymorphic site in the region containing GMDS, the polymorphic site in the region containing GMDS of human chromosome 6, the polymorphic site in the region containing 6p21.3 of human chromosome 6 (including HSPA1B), and SYTL3 of human chromosome 6
  • the marker gene of the present invention is usually 10 bases or longer, preferably 20 bases or longer. For example, it may be 50 base length, 100 base length, 200 base length, 300 base length, 600 base length, 1000 base length or the like including the polymorphic site.
  • the ORF of the gene the region controlling the expression of the gene (for example, promoter region, enhancer region, etc.) can be determined.
  • the amino acid sequence of the polypeptide encoded by ORF can be determined.
  • the polypeptide encoded by the DNA sequence of the marker gene of the present invention is obtained by culturing host cells transformed with a vector containing the DNA sequence (or at least a fragment thereof containing a translation region), and culturing the polypeptide from the culture. Can be produced.
  • the present invention also provides a vector containing the DNA sequence of the marker gene of the present invention and a host cell transformed with the vector.
  • the DNA sequence of the marker gene of the present invention can be produced, for example, as follows. MRNA is extracted from a human biological sample (for example, blood of a healthy person or a patient), and cDNA is synthesized using reverse transcriptase and oligo dT primer. Using this as a template, the marker gene of the present invention is amplified by PCR.
  • a vector (recombinant vector) containing the DNA sequence of the marker gene of the present invention can be obtained by a known method (for example, the method described in Molecular Cloning 2nd Edition, J. Sambrook et al., Cold Spring Harbor Lab. Press, 1989). It can be obtained by inserting the DNA sequence of the marker gene of the present invention into an appropriate expression vector.
  • plasmids derived from E. coli eg, pBR322, pBR325, pUC12, pUC13
  • plasmids derived from Bacillus subtilis eg, pUB110, pTP5, pC194
  • yeast-derived plasmids eg, pSH19, pSH15
  • ⁇ phage etc.
  • Bacteriophages, animal viruses such as retroviruses and vaccinia viruses, insect pathogenic viruses such as baculoviruses, and the like can be used.
  • a promoter, enhancer, splicing signal, poly A addition signal, selection marker, SV40 replication origin, etc. may be added to the expression vector.
  • the expression vector may be a fusion protein expression vector.
  • fusion protein expression vectors are commercially available: pGEX series (Amersham Pharmacia Biotech), pET CBD Fusion System 34b-38b (Novagen), pET Dsb Fusion Systems 39b and 40b (Novagen), pET GST Fusion System 41 and 42 (Novagen).
  • a transformant can be obtained by introducing a vector (recombinant vector) containing the DNA sequence of the marker gene of the present invention into a host cell.
  • Host cells include bacterial cells (eg, Escherichia, Bacillus, Bacillus, etc.), fungal cells (eg, yeast, Aspergillus, etc.), insect cells (eg, S2 cells, Sf cells, etc.), animal cells ( Examples thereof include CHO cells, COS cells, HeLa cells, C127 cells, 3T3 cells, BHK cells, HEK293 cells), plant cells, and the like.
  • bacterial cells eg, Escherichia, Bacillus, Bacillus, etc.
  • fungal cells eg, yeast, Aspergillus, etc.
  • insect cells eg, S2 cells, Sf cells, etc.
  • animal cells examples thereof include CHO cells, COS cells, HeLa cells, C127 cells, 3T3 cells, BHK cells, HEK293 cells
  • plant cells and the like.
  • the transformant can be cultured in a medium, and the polypeptide encoded by the DNA sequence of the marker gene can be collected from the culture.
  • the medium may be recovered, the polypeptide separated from the medium, and purified.
  • the polypeptide is produced in a transformed host cell, the cell may be lysed, the polypeptide separated from the lysate and purified.
  • the polypeptide When the polypeptide is expressed in the form of a fusion protein with another protein (functioning as a tag), the fusion protein is separated and purified, and then treated with FactorXa or an enzyme (enterokinase).
  • the target polypeptide can be obtained by cleaving the protein.
  • Separation and purification of the polypeptide can be performed by known methods.
  • Known separation and purification methods include methods that utilize differences in solubility such as salting out and solvent precipitation, dialysis, ultrafiltration, gel filtration, and SDS-polyacrylamide gel electrophoresis.
  • Method utilizing difference method utilizing charge difference such as ion exchange chromatography, method utilizing specific affinity such as affinity chromatography, method utilizing hydrophobic difference such as reverse phase high performance liquid chromatography
  • NTG is considered to be a multifactorial disease that increases the risk of onset due to a large number of many genetic factors.
  • MYOC, OPA1 and OPTN genes have been reported as susceptibility genes for glaucoma including NTG, but these are only found in a few percent of glaucoma patients and show little correlation in Japanese. . Therefore, in order to comprehensively identify the NTG disease susceptibility genes, the present inventor analyzed all 500,000 SNPs at a high throughput at a time using the GeneChip Mapping 500k Array set of Affymetrix. Exhaustive genetic screening for genomic regions was performed. In addition, because the analysis data of this study is enormous and cannot be handled by conventional databases, we developed a database for SNP analysis that supports correlation analysis using a large amount of SNP.
  • SNP typing output file of Gene Chip 250k and 500k can be input as database input file
  • SNP ID and rs used in GTYPE It is possible to manage the correspondence with number, position information, neighboring gene information, and allele type known allele information (Hapmap), and (iii) Haploview and other input text formats for various analysis software can be arbitrarily specified and obtained as an output file
  • a database that can search, sort, extract and display registered data and analysis results has been constructed.
  • the DNA concentration was quantified using a PicoGreen quantification kit (PicoGreen ds DNA Quantification Reagent and Kit 200-2000 assay) to prepare a uniform DNA concentration for each sample. Thereafter, the whole genome was cleaved with a restriction enzyme, and an adapter recognizing a specific protruding terminal of 4 bases was ligated. The DNA fragment to which the adapter was added was amplified by PCR, fragmented and labeled, and then hybridized to Mapping 250k Array.
  • PicoGreen quantification kit Pieric Acids DNA Quantification Reagent and Kit 200-2000 assay
  • the alleles of each SNP were analyzed from the fluorescence intensity of each probe with a laser scanner using the Direct Model (DM) Algorithm. Based on the obtained results, the allele distribution of the patient group and the healthy group is statistically analyzed for each SNP, and the genes that correlate with the disease are determined. Experimental accuracy and contamination were evaluated using modified partitioning aroundmethods (MPAM) algorithm. SNP typing using Affymetrix GeneChip (registered trademark) mapping 500k array was completed for 266 NTG patients. The SNP call rate (the proportion of SNPs that were analyzed properly) averaged over 95% for both NspI and StyI arrays, indicating good typing accuracy.
  • MPAM modified partitioning aroundmethods
  • Rs Id represents the rs number
  • Chromosome represents the chromosome
  • Position represents the NCBI (v36.1) number
  • Astat2 P Value (2x2) represents the p value.
  • the present invention can be used for life science, medicine, ophthalmology and diagnosis.
  • Takahashi H, Ohtake Y, Kubota R, et al. [Two families with primary open-angle glaucoma associated with myocilin gene mutations].

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Abstract

La présente invention concerne un gène sensible à une maladie de glaucome à pression normale. La présente invention concerne en outre un procédé pour utiliser le gène. Une analyse/comparaison complète a été effectuée sur des polymorphismes de nucléotide unique sur le génome entier chez de nombreux patients atteints de glaucome à pression normale et de nombreuses personnes normales, et il a été observé qu’il existe une différence de sites de polymorphisme présents dans les régions contenant ELOVL5 sur le chromosome 6 humain et similaires parmi les patients et les personnes normales, où les sites de polymorphisme sont représentés par les numéros de polymorphisme de nucléotide unique internationaux rs222450, rs9474394, rs2816344, rs2816341, rs2518579, rs2518578, rs9367511, rs6915699, rs6930045, rs9370188, rs9382180, rs9382181, rs4486010, rs2816379, rs6939730, rs2817088, rs2817090, rs2816372, rs2562895, rs2816364, rs2562893, rs2817101, rs2816362, rs2816356, rs10948744, rs12183976, rs2562898, rs735860, rs715441, rs2057024, rs1429146, rs9463895, rs2235723, rs1346603, rs9474476, rs2294867, rs9349660, rs974323, rs6909592, rs9367520, rs9395854, rs209485, rs9395856, rs7747926, rs7738788, rs209500, rs9357760, rs9370196, rs209512, rs209517, rs9370201, rs9367529, rs12209741, rs7744451, rs6904083, rs6904376, rs9367532, rs2067833, rs9382212, rs2139077, rs2397146, rs7742367, rs9474576, rs622447, rs3736729, rs13212365 et rs761141.  Il devient possible de diagnostiquer le glaucome à pression normale sur la base de la différence dans ces sites de polymorphisme.
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WO2011148715A1 (fr) * 2010-05-26 2011-12-01 株式会社メニコン Gène de susceptibilité au glaucome à pression normale et procédé de son utilisation
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CN113430263B (zh) * 2021-08-27 2021-11-05 中国医学科学院北京协和医院 基于生物标志物的诊断青光眼的产品及其应用

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