JP6245796B2 - Markers, probes, primers and kits for predicting the risk of developing primary biliary cirrhosis and methods for predicting the risk of developing primary biliary cirrhosis - Google Patents

Description

  The present invention relates to markers for predicting the risk of developing primary biliary cirrhosis, probes, primers and kits, and methods for predicting the risk of developing primary biliary cirrhosis.

  It is known that disease susceptibility, that is, susceptibility to a specific disease, is influenced by genetic predispositions as well as constitutions such as height, weight, and nose height. One of the main methods for examining such genetic predisposition is to use a single nucleotide polymorphism (SNP) of a gene. In the search for genetic predisposition using the conventional candidate gene method SNP, depending on the conventional candidate gene method, only SNPs of genes suspected to be involved in the onset of the disease could be examined one by one. Recently, a genome-wide association study (GWAS) has been developed as a method for comprehensively examining these SNPs. GWAS is a method of setting hundreds of thousands to millions of SNPs on all chromosomes and using them as markers to search for regions on the chromosome that are related to a certain disease or trait. Genes related to diseases and traits have been identified.

  On the other hand, in recent years, genome-wide association analysis (GWAS) has identified HLA, IL12A, IL12RB2, IRF-TNPO, chromosome 17q12-21 and the like as disease susceptibility genes for primary biliary cirrhosis (PBC) in Westerners (for example, Non-patent documents 1 to 4).

Hirschfield, G.M., et al., "Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.", N. Engl. J. Med., 360 (2009), 2544-2555. Hirschfield, G.M., et al., "Variants at IRF5-TNPO3, 1 7ql2-21 and MMEL1 are associated with primary biliary cirrhosis.", Nat. Genet., 42 (2010), 655-657. Liu, X., et al., "Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis.", Nat. Genet., 42 (2010), 658-660. Mells, G.F., et al., "Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet., 43 (2011), 329-332.

  However, as a result of intensive studies on the disease susceptibility genes, particularly the PBC susceptibility genes, the present inventor has found that there are considerable racial differences in PBC susceptibility genes, and Asian PBC patients have been identified in Western PBC patients. In addition, the present inventors have found that a disease susceptibility gene different from the above-described disease susceptibility gene may exist. Therefore, an object of the present invention is to identify a disease susceptibility gene specific to Asian PBC patients by GWAS.

  Another object of the present invention is to provide a novel PBC development risk prediction marker, probe, primer and kit, and a PBC development risk prediction method.

  The above object of the present invention is achieved by the following means.

(1) That is, the present invention is at least one selected from the group consisting of the following single nucleotide polymorphisms and linkage disequilibrium with oligonucleotides or polynucleotides existing on the human genome. It is a marker for predicting the risk of developing primary biliary cirrhosis.
rs12552933, rs6478106, rs10114470, rs16931745, rs6478108, rs4979462, rs7869487, rs2006996, rs7040029, rs998410, rs7866342, rs7863183, rs13300483, rs7028891, rs1407309, rs911605, rs10982445, rs5003740, rs3181201, rs3181372, rs3181367, rs3181195, rs3827818, rs1555457, rs2075533, rs1944919, rs4938534, rs4574992, rs3789878, rs1046872, rs79479952, rs5020096, rs7107344, s4938459, rs7104791, rs6589221, rs12574149, rs17471196, rs12291412, rs1986838, rs12803295, rs10502139, rs10502143, rs1815949, rs7118200, rs1815945, rs12146590, rs7111520, rs4356268, rs12800302, rs883326, rs1806397, rs7952176, rs17577003, rs4938535, rs7115223, rs17577362, rs10891264, rs4393359, rs4938590, rs7930326, rs125550920, rs7856856, rs78771089, rs7860414, rs 6931675, rs13288059, rs7857786, rs7862402, rs10982408, rs7853287, rs7871609, rs1891836, rs12682881, rs12682886, rs16931739, rs12682952, rs3810936, rs16931748, rs4246905, rs16931761, rs12336261, rs7867918, rs12235514, rs6478107, rs7847158, rs4322082, rs4372078, rs4366152, rs4263839, rs7048850, rs7862325, rs7030574, rs10982410, rs10982411, rs64478109, rs7848641, rs7 848647, rs7862688, rs7865612, rs1407308, rs10982412, rs10982413, rs11793394, rs12002641, rs727844, rs12237626, rs7865494, rs7866570, rs7866379, rs1322057, rs10817678, rs17219926, rs4144344, rs12290806, rs4600249, rs11213845, rs7949014, rs12279781, rs11213846, rs7481296, rs4641517, rs 10502140, rs 10502141, rs 10502142, rs 7124208, rs 12793177, rs 12272263, rs 1042752, r 6589223, rs11213848, rs7107546, rs11213850, rs10891258, rs11213851, rs12786652, rs4514461, rs4387383, rs11213852, rs7944695, rs12271713, rs1815950, rs2282637, rs11213854, rs11213855, rs2002367, rs7110111, rs1815948, rs11603490, rs1806434, rs11213857, rs1815946, rs4408345, rs4547134, rs7116862, rs12419634, rs12419617, rs11213858, rs111605031, rs4405350, rs1815947 rs4529910, rs7108287, rs12799202, rs12799546, rs4245181, rs4245182, rs4938509, rs7950136, rs6589224, rs4489781, rs4283016, rs6421552, rs6589226, rs6589228, rs6589229, rs11213861, rs3802844, rs4565931, rs11213864, rs4529913, rs11213865, rs4938510, rs11213867, rs9666506, rs12286832, rs7925321

  (2) In the present invention, the single nucleotide polymorphisms are rs1255523, rs64778106, rs10114470, rs169931745, rs64478108, rs4979462, rs78669487, rs7869342, rs7386342, rs7386342, rs7386342, rs7386342, rs7386342, rs , Rs3181201, rs3181372, rs3181367, rs31818195, rs3827818, rs1555457, rs20755533, rs19444919, rs4938534, rs4577891, rs3789878, rs1046872, rs7949472, rs 5020096, rs7107344, rs4938459, rs7104791, rs6589221, rs12574149, rs17471196, rs12291412, rs1986838, rs12803295, rs10502139, rs10502143, rs1815949, rs7118200, rs1815945, rs12146590, rs7111520, rs4356268, rs12800302, rs883326, rs1806397, rs7952176, rs17577003, rs4938535, rs7115223, rs17577362, rs10891264, rs4393359, rs4938590, rs7930326, rs7856856, or rs13222057, 1) a risk predictive marker for primary biliary cirrhosis described.

  (3) The present invention is also the risk prediction marker for primary biliary cirrhosis according to (1), wherein the single nucleotide polymorphism is rs64478106, rs49794462, rs4938534, rs7856856 or rs13222057.

  (4) The present invention is also a marker for predicting the risk of developing primary biliary cirrhosis according to any one of (1) to (3), which is for Asians.

  (5) The present invention is also a marker for predicting the risk of developing primary biliary cirrhosis according to any one of (1) to (3), which is for Japanese.

  (6) The present invention is also selected from the group consisting of the single nucleotide polymorphisms described in (1) to (5) and those in linkage disequilibrium with oligonucleotides or polynucleotides present on the human genome It is an oligonucleotide or polynucleotide characterized by hybridizing with at least one of the above or a label thereof.

  (7) The present invention is also a probe for predicting the risk of developing primary biliary cirrhosis, comprising the oligonucleotide or polynucleotide according to (6) or a labeled product thereof.

  (8) The present invention is also a primer for predicting the risk of developing primary biliary cirrhosis, comprising the oligonucleotide or polynucleotide according to (6) or a labeled product thereof.

  (9) The present invention is also a risk prediction kit for primary biliary cirrhosis characterized by comprising the probe according to (7) and / or the primer according to (8).

  (10) The present invention also provides (a) at least one genotype of a single nucleotide polymorphism according to (1) to (5) or a linkage disequilibrium with a specimen collected from a human individual. And (b) determining the risk of development of primary biliary cirrhosis in the human individual based on the genotype determined in step (a). This is a method for predicting the risk of developing cirrhosis.

  According to the PBC onset risk prediction marker, probe, primer, and kit of the present invention and the PBC onset risk prediction method, the PBC onset risk can be predicted extremely easily, inexpensively, and accurately.

  Hereinafter, the present invention will be described in detail.

PBC risk prediction marker

  The marker for predicting the risk of developing PBC of the present invention is at least selected from the group consisting of a specific single nucleotide polymorphism (SNP) and a linkage disequilibrium with these oligonucleotides or polynucleotides existing on the human genome. It consists of what contains 1 type.

  Here, in the present invention, the marker is a gene or gene fragment present in a sample such as blood of a subject who is suspected of developing PBC, and is detected by a probe or the like described later, and the gene By examining the type (gene polymorphism such as SNP), it becomes a sample for predicting the onset risk of PBC.

  In the present invention, “gene”, “oligonucleotide” or “polynucleotide” refers to purine bases such as adenine (A) and guanine (G), thymine (T), uracil (U), cytosine (C ), Etc., and their modified bases as constituents, consisting of single-stranded or double-stranded DNA, single-stranded or double-stranded RNA, single-stranded DNA and single-stranded RNA It means a hybrid, a chimera in which RNA and DNA are combined to form a single strand, or a combination thereof, and DNA includes cDNA.

  The SNP used in the PBC risk marker of the present invention includes SNFs of TNFSF15 and POU2AF1, rs1255523, rs64478106, rs101114470, rs169931745, rs64478108, rs4979462, rs7869387, rs994633, rs99630029, rs994630029, rs994630029, rs994630029, rs99634 , Rs7028891, rs1407309, rs911605, rs10982445, rs5003740, rs3181811, rs3181812, rs318181367, rs31818195, rs3827818, rs1555557, rs2075533, rs19438419, rs4938534, rs4938534 574921, rs3789878, rs1046872, rs7947952, rs5020096, rs7107344, rs4938459, rs7104791, rs6589221, rs12574149, rs17471196, rs12291412, rs1986838, rs12803295, rs10502139, rs10502143, rs1815949, rs7118200, rs1815945, rs12146590, rs7111520, rs4356268, rs12800302, rs883326, rs1806397, rs7952176, rs17577003, rs4938535, rs71515223, rs17577362, rs10891264, rs4393359, rs493 590, rs7930326, rs12550920, rs7856856, rs7871089, rs7860414, rs16931675, rs13288059, rs7857786, rs7862402, rs10982408, rs7853287, rs7871609, rs1891836, rs12682881, rs12682886, rs16931739, rs12682952, rs3810936, rs16931748, rs4246905, rs16931761, rs12336261, rs7867918, rs12235514, rs6478107, rs7847158, rs4322082, rs4372078, rs4366152, rs4263839, rs7048850, rs78623 25, rs7030574, rs10982410, rs10982411, rs6478109, rs7848641, rs7848647, rs7862688, rs7865612, rs1407308, rs10982412, rs10982413, rs11793394, rs12002641, rs727844, rs12237626, rs7865494, rs7866570, rs7866379, rs1322057, rs10817678, rs17219926, rs4144344, rs12290806, rs4600249, rs11213845, rs7949014, rs122799781, rs11213846, rs7481296, rs4641517, rs10502140, rs10502 41, rs10502142, rs7124208, rs12793177, rs12272263, rs1042752, rs6589223, rs11213848, rs7107546, rs11213850, rs10891258, rs11213851, rs12786652, rs4514461, rs4387383, rs11213852, rs7944695, rs12271713, rs1815950, rs2282637, rs11213854, rs11213855, rs2002367, rs7110111, rs1815948, rs11603490, rs1806434, rs11213857, rs1815946, rs4408345, rs4547134, rs7116862, rs124 9634, rs12419617, rs11213858, rs11605031, rs4405350, rs1815947, rs4529910, rs7108287, rs12799202, rs12799546, rs4245181, rs4245182, rs4938509, rs7950136, rs6589224, rs4489781, rs4283016, rs6421552, rs6589226, rs6589228, rs6589229, rs11213861, rs3802844, rs4565931, rs11213864, rs4529913, rs11213865, rs4938510, rs11213867, rs96666506, rs12286832, rs7925321, and the like. However, the number (rs number) representing the above SNP represents the reference number of the SNP database of NCBI (National Center for Biotechnology Information).

  Among these SNP, rs12552933, rs6478106, rs10114470, rs16931745, rs6478108, rs4979462, rs7869487, rs2006996, rs7040029, rs998410, rs7866342, rs7863183, rs13300483, rs7028891, rs1407309, rs911605, rs10982445, rs5003740, rs3181201, rs3181372, rs3181367, rs3181195 , Rs3827818, rs1555557, rs2075533, rs19444919, rs4938534, rs4574992, rs3789878, rs1046872, rs79447952, rs502009 , Rs7107344, rs4938459, rs7104791, rs6589221, rs12574149, rs17471196, rs12291412, rs1986838, rs12803295, rs10502139, rs10502143, rs1815949, rs7118200, rs1815945, rs12146590, rs7111520, rs4356268, rs12800302, rs883326, rs1806397, rs7952176, rs17577003, rs4938535, rs7115223, rs17577362 , Rs10891264, rs4393359, rs4938590, rs7930326, rs7856856 and rs13222057 are preferred as markers. , Among them, rs6478106, rs4979462, rs4938534, rs7856856 or rs1322057 is, since the P value is an important indicator of the risk is considered to be high small risk, particularly preferred as an important marker. However, the P value has the same meaning as the significance probability, and is a probability value for indicating the significance of the statistical test.

  Moreover, what is in a linkage disequilibrium state with the SNP is a linkage disequilibrium state (R2> 0.8) with the SNP, and is capable of predicting the risk of developing PBC similar to the SNP. Detection can be performed according to a known method using Haploview software or the like.

  The marker of the present invention may be any oligonucleotide or polynucleotide containing at least one of the SNPs described above, and a plurality of SNPs may be present in one oligonucleotide or polynucleotide. It may exist separately in the polynucleotide.

  Since SNPs are often linked, it is preferable to consider after creating a haplotype by combining not only one SNP but also a plurality of closely linked SNPs. For example, by testing in combination with a tag (representative) SNP that expresses a haplotype in this marker (gene), the prediction of the risk of developing PBC can be made more efficient and reliable.

  The size of the oligonucleotide or polynucleotide of the marker of the present invention is preferably 40 k base length (or base pair (bp)) or less, more preferably 16 k base length (or bp) or less, and 1500 to 3000 base length (or bp). Is particularly preferred.

  The PBC risk marker that includes these oligonucleotides or polynucleotides can be extracted from the subject sample and purified as necessary, and can be used as an oligonucleotide or polynucleotide, but is present in the obtained sample. When the gene or gene fragment is mRNA, it can be used as a cDNA for reverse transcriptase and as a PBC risk marker.

  The marker for predicting the risk of developing PBC according to the present invention is useful for Japanese, Chinese, Korean, Taiwanese, Asian PBC patients including races in Southeast Asian countries, and particularly suitable for Japanese PBC patients. Can be used.

Oligonucleotide or polynucleotide or label thereof

  The oligonucleotide or polynucleotide of the present invention or the label thereof is an oligonucleotide or polynucleotide existing on the human genome, and consists of the single nucleotide polymorphism according to the marker of the present invention and a linkage disequilibrium with these. It hybridizes with what contains at least 1 selected from a group.

  Since the oligonucleotide or polynucleotide of the present invention or a labeled product thereof has a property of hybridizing to the region containing the single nucleotide polymorphism, the gene in a patient sample is amplified when predicting the risk of developing PBC. It can be used as a probe for picking up the predictive marker of the present invention from the primers used in the above or from the amplified gene.

  Here, the label is a substance that facilitates detection of the target marker gene by binding to a probe, primer, or the like, and examples thereof include biotin, digoxigenin, radioactive label, enzyme label, and fluorescent label. It is done. The label can be bound to the oligonucleotide or polynucleotide according to a known method.

Probe for predicting PBC risk

  The probe for predicting the risk of developing PBC of the present invention comprises the oligonucleotide or polynucleotide of the present invention or a label thereof.

  Here, the probe refers to a probe that is used to pick up a specific oligonucleotide or polynucleotide and specifically hybridizes with an oligonucleotide or polynucleotide that is a detection target.

  Since the probe of the present invention is composed of the oligonucleotide or polynucleotide of the present invention or a labeled product thereof and has a property of hybridizing to the region containing the single nucleotide polymorphism, a marker is used when predicting the risk of developing PBC. Can be used to detect oligonucleotides or polynucleotides corresponding to.

  The probe of the present invention can be appropriately designed so as to hybridize with the nucleotide sequence of the oligonucleotide or polynucleotide (marker) to be detected. The probe sequence preferably forms a completely complementary pair with the target base sequence, but it only needs to be homologous to the completely complementary pair to the extent of hybridization. The size of the probe varies depending on the oligonucleotide or polynucleotide to be detected, and cannot be generally specified, but is preferably 1000 base length or less, more preferably 5 to 500 base length, and particularly preferably 10 to 40 base length. It is about the base length. In general, DNA is suitable as the probe from the viewpoint of the stability of the nucleic acid molecule, but a chimeric probe is used when the target is amplified using a kind of cycling probe method in the real-time PCR method.

  Specific examples of the probe of the present invention include those described in Tables 1 and 2 described later.

Primer for PBC risk marker

  The primer for predicting the risk of developing PBC of the present invention comprises the oligonucleotide or polynucleotide of the present invention or a label thereof.

  Here, the primer is used for amplifying a specific oligonucleotide or polynucleotide, and the 3 ′ end of the antisense strand and the sense strand of the oligonucleotide or polynucleotide to be detected, A sense (forward) primer and an antisense (reverse) primer that specifically hybridize with each other.

  Since the primer of the present invention is composed of the oligonucleotide or polynucleotide of the present invention or a labeled product thereof and has a property of hybridizing to the region containing the above single nucleotide polymorphism, a sample is used when predicting the risk of developing PBC. An oligonucleotide or polynucleotide corresponding to the marker in it can be amplified and used to facilitate detection.

  The primer of the present invention can be appropriately designed according to the base sequence at the end of the oligonucleotide or polynucleotide (marker) to be detected. The primer sequence is preferably one that completely forms a complementary pair with the target base sequence, but may be homologous to the complete complementary pair to the extent that it hybridizes with the target. The size of the primer varies depending on the oligonucleotide or polynucleotide that is the target of detection and cannot be generally specified. For example, the primer length is 5 to 100 bases, preferably 10 to 70 bases, more preferably 15 to 50 bases. What is necessary is just to be long. In general, DNA is suitable as the primer from the viewpoint of the stability of the nucleic acid molecule, but a chimeric primer is used in the isothermal gene amplification method (ICAN method).

  Specific examples of the primer of the present invention include those described in Tables 1 and 2 described later.

PBC risk prediction kit

  The PBC onset risk prediction kit of the present invention comprises the above-described probe and / or primer of the present invention.

  That is, the PBC onset risk prediction kit of the present invention is a kit used for predicting the risk of onset of PBC. In addition to the probe of the present invention and the primer of the present invention, reagents necessary for PCR (heat-resistant) are necessary. DNA polymerase), devices, reagents, software, computers and the like generally required for genotyping may be included as appropriate.

PBC risk prediction method

  The method for predicting the risk of developing PBC according to the present invention comprises: (a) using a sample collected from a human individual to obtain at least one genotype of a single nucleotide polymorphism related to the marker of the present invention or a linkage disequilibrium with them. And (b) determining the risk of developing PBC of the human individual based on the genotype determined in step (a).

  In the prediction method of the present invention, first, in step (a), a specimen is collected from a human individual such as a patient. Here, the specimen means blood, serum, lymph, semen, urine, saliva (including oral mucosal cells), other body fluids, biological tissues, and the like. Among these, blood (lymphocytes) is preferable in that it is most easily collected and is less invasive.

  Next, an oligonucleotide or polynucleotide is prepared from the obtained specimen. Examples of the oligonucleotide or polynucleotide include cDNA prepared by reverse transcriptase based on genomic DNA or mRNA. When the gene polymorphism is accompanied by amino acid substitution, it is possible to confirm the genotype using the protein obtained based on the nucleic acid.

  Preparation of the oligonucleotide or polynucleotide may be carried out according to a known method. However, when the oligonucleotide or polynucleotide is DNA, for example, from a blood cell such as lymphocyte or granulocyte in the blood sample, Analysis, a PCI (phenol chloroform extraction) method, a method using a commercially available DNA extraction kit, and the like, and other known methods. When the oligonucleotide or polynucleotide is mRNA, the PCI method is used to acidify the solution and extract from the aqueous layer, the method using an oligo dT column, etc., the method using a commercially available RNA extraction kit, and other known methods Can be used.

  When the amount of nucleic acid obtained from the specimen is small, it can be amplified by a known method as necessary. For example, the PCR method or the like can be used when the nucleic acid is DNA, and the RT-PCR method can be used when the nucleic acid is mRNA. As the quantitative PCR method, a real-time PCR method using a TaqMan probe or SYBR Green (Power SYBR) can also be used.

  Next, the genotype of the gene polymorphism part is determined using the obtained nucleic acid. As a method for determining a genotype, a known sequencing method or the like can be used. For example, in addition to a direct sequencing method (dideoxy method) in which a base sequence is directly determined using a sequencer or the like, RELP (restriction enzyme fragment length polymorphism) PCR-RELP method, TaqMan method, DigiTag2 method, single nucleotide primer extension method, SnaPshot method (ABI), ASP-PCR method, PCR-SSO (Sequence specific oligonucleotide) method, PCR-SSP (Specispeci ce) ) Method, PCR-SSCP (Single-stranded conformation polymorphism analysis) method, confirmation of nucleic acid length by electrophoresis, etc., and D A method using an A chip, etc. polymorphisms testing instrument, and the like, but not limited to.

  And in a process (b), PBC onset risk can be estimated by referring to Table 1 and Table 2 mentioned below based on the genotype information obtained at the process (a). That is, when a risk allele of each SNP is detected in a sample obtained from a human individual, the human individual has a higher risk of developing PBC, and in particular, the more a risk allele of a SNP with a low P value is, The risk of developing primary biliary cirrhosis is considered high.

Identification of disease susceptibility gene of PBC by GWAS

  PBC disease susceptibility genes of PBC1327 cases and 1120 healthy individuals who were diagnosed after 1980 were identified by GWAS.

  First, PBC512 cases (clinical stage I: 343, II: 114, III: 55, AMA positive 88.6%, gp210 antibody positive 34.5%, centromer antibody positive 26.7% registered in the NHO liver disease network , AIH merged 5.1%) and 500 healthy controls, GWAS was performed using Affymetrix Axiom Genome-Wide ASI 1 Array (AxiomASI). This array is specialized for Asians, and it is possible to genotype 600,000 SNPs at a frequency of 1% or more in the HapMap JPT (Japanese) + CHB (Chinese) genome at once. is there. In AxiomASI, 200 ng of DNA was amplified, and the amplified product was randomly fragmented to a length of 25 to 125 bases. It was then purified and hybridized to AxiomASI Plates and the bound target was washed under harsh conditions. Next, a probe specifically labeled for A / T and G / C was ligated, the array was stained (intensified signal), and then imaged as an image on GeneTitan MC Instrument. Genotyping of each polymorphism was performed using Genotyping Console Software based on fluorescence intensity. After removing polymorphisms considered to be poor typing (SNP Call rate <0.95, Hardy-Weinberg equilibrium P <0.001), Chi-square test (allelic model) can be used to determine the association with disease. investigated. For SNPs with a P value calculated by chi-square test of less than 0.001, check the clustering status of each genotype at the time of genotype determination, and exclude SNPs that are suspected to have errors at the time of genotype determination It was.

  Next, SNPs that showed a strong association with the presence or absence of the disease were registered with the Ministry of Health, Labor and Welfare "Survey Research Group on Refractory Liver / Biliary Disease" and "Research Group on Collection of Biological Samples of Refractory Liver Disease" Replication analysis was performed by the DigiTag2 method using PBC815 cases and 620 healthy controls. At the same time as the typing of the additional specimen, a confirmation experiment of the specimen used in the GWAS was also performed to confirm that it was not a false positive due to a typing error. The DigiTag2 method is a medium-scale typing tool that can perform typing of 32 SNPs (32 samples) or 96 SNPs (24 samples) at a time. Multiplex PCR was performed using 25 ng of DNA as a template, and polymorphism-specific ligation reaction was performed using the amplification product as a template. Thereafter, the ligation product was amplified, finally hybridized to a DNA microarray, and the fluorescence intensity of each was measured to determine the allele of each SNP.

  The analysis results of 96 SNPs analyzed by GWAS are shown in Tables 1-3. From these results, SNPs present in the gene regions of TNFSF15 and POU2AF1 identified as susceptibility genes peculiar to Japanese PBC patients, which are considered to be highly important among those registered in public databases SNPs are also shown in Tables 4-7.

Further, specific primer sequences of SNPs in Tables 1 to 3 are shown as SEQ ID NOs: 1 to 192, and specific probe sequences are shown as SEQ ID NOs: 193 to 480 in Tables 8 to 10. However, the primer or probe of the present invention is not limited to these, and one to several nucleotides of these sequences are deleted, substituted, added, and / or inserted. Needless to say, the primers and probes of the present invention also include those that can hybridize with the marker. These primers and probes are DNA as shown in the sequence listing, but may be RNA having the same base, or a chimera of DNA and RNA. However, DNA is preferable from the viewpoint of stability and the like.

In Tables 1-7, SNP001-SNP026, SNP063, and SNP064 are SNF of TNFSF15 which is a susceptibility gene peculiar to the Japanese PBC patient identified in the present Example, and SNP097-SNP148 exists in the gene region. An SNP that is registered in a public database. These SNPs have already been reported by Westerners and Japanese as a disease susceptibility gene in Crohn's disease and ulcerative colitis, but there is no report related to the onset of PBC. Among these, rs4979462 (SNP007) which showed the strongest correlation (P = 7.26 × 10 ⁻⁸ ), rs6478106 (SNP002), rs7858566 (SNP098), rs13222057 which showed LD (r ² )> 0.8. (SNP146) is considered to be extremely important as a predictive marker for the risk of developing PBC.

  Although TNFSF15 has been reported to be highly expressed in lesions of Crohn's disease and ulcerative colitis, the present inventors have confirmed that TNFSF15 expression is also increased in the PBC liver region. Thus, it is presumed that the TNFST15 SNP identified in this example is involved in the onset of PBC via a change in the expression of TNFSF15. This suggests that the development of a therapeutic method using TNFSF15 as a molecular target can be a radical treatment of PBC. The marker of the present invention and a probe using the marker of the present invention for the identification of a case at risk of developing TNFSF15 Primers may be very useful tools.

In Tables 1 to 7, SNP027, SNP028, SNP065 to SNP096 are POU2AF1 SNPs that are unique to Japanese PBC patients identified in this Example, and SNP149 to SNP222 are present in the same gene region. An SNP that is registered in a public database. POU2AF1 has never been reported as a disease susceptibility gene. Among these, rs4938534 (SNP028), which showed the strongest correlation (P = 5.22 × 10 ⁻⁶ ), is considered to be extremely important as a predictive marker for the onset risk of PBC.

  POU2AF1 is an essential transcription factor for differentiation and maturation of B lymphocytes. The results of this example suggest that B lymphocytes are involved in the development of PBC, and a therapeutic method using POU2AF1 as a molecular target. This suggests that development is necessary. In addition, POU2AF1 may be a molecular target for treatment in other autoimmune diseases such as SLE and RA that have been reported to be involved in disease development of B lymphocytes. It may be possible to perform large-scale screening for autoimmune diseases other than PBC using probes and / or primers.

  As described above, since the marker of the present invention and the probe and / or primer using the marker can predict the risk of developing PBC very easily, inexpensively, and accurately, it was used as a kit for predicting the risk of developing PBC. It is extremely useful in some cases.

Sequence number 1: sense primer for SNP001: AGTCATGAAGCACTGTTTCTACTAGGTTCTATAATCAAAGTA
Sequence number 2: antisense primer for SNP001: CACCCAAGTAGAGTACAGTGTACCTAAAATGTAGTTTCTA
Sequence number 3: sense primer for SNP002: TGGCGTCTGTTCCGATTTGTTAGATGTGATTCTGATTA
Sequence number 4: antisense primer for SNP002: TCCCCATATATCAGCTGGAGAGCTTTGCAGTCTAA
Sequence number 5: sense primer for SNP003: TTCTACTGTAGCTCCCCAGAGAAGAGAGCTAGGGCTA
Sequence number 6: antisense primer for SNP003: CCCCTGAAACAAAAAAAGGGGAACATTACATGCTTTAATGA
Sequence number 7: sense primer for SNP004: TTTTCAGGTCAGACCACTCAGTCTCAGAAAGGCAAA
Sequence number 8: antisense primer for SNP004: GCCCCAAGAAAACCCCTGGTTATAATTACATTTGAACAAA
Sequence number 9: sense primer for SNP005: TTTTCAGGTCAGACCACTCAGTCTCAGAAAGGCAAA
Sequence number 10: antisense primer for SNP005: GCCCCAAGAAAACCCCTGGTTATAATTACATTTGAACAAA
Sequence number 11: sense primer for SNP006: TTCCAACTACTCCCATGTCCTGTTGAGCCTCCTTA
Sequence number 12: antisense primer for SNP006: CTGCCTTCAGAGGGCTTTTTCTAAAGCATCACTTTATCTA
Sequence number 13: sense primer for SNP007: GGATGCTATAATTTCTTTACCCACTCTTTTTCTTGGGTTTAGAA
Sequence number 14: antisense primer for SNP007: TCTGACTTCCCATGACCTGCGGTTCTTCTTTAACATAAA
Sequence number 15: sense primer for SNP008: AAATTGCAAGCTGGCTGTCTGGAACCTTAACAGTA
Sequence number 16: antisense primer for SNP008: CATCACGAACTTGCTATGTGACTTCAGGCTGTTCA
Sequence number 17: sense primer for SNP009: GCCCAAATCTTCCGATAACTGAAAAACATCCATATTTGAATA
Sequence number 18: antisense primer for SNP009: TTTTCTCAATTTGTGGTTTTTGCTTGGGTTTGTGGTTTA
Sequence number 19: sense primer for SNP010: AAATCTCCAAACTGCTTCCCTGAACTAACTTACATTCCTA
Sequence number 20: antisense primer for SNP010: CCACAAGTTTTAACAAATCGGTTTGAACAAATAACTTATA
Sequence number 21: sense primer for SNP011: GTTGATGGATTAATGCAAACAATGTACTTTTATGAAGAATAA
Sequence number 22: antisense primer for SNP011: GCTGTAACACTCTAACATCCAAGGATTTATCCTAGTCTGATAAA
Sequence number 23: sense primer for SNP012: AGCCTATGGTATTCCTTTATAGCAATGCAAAACGGAGTAA
Sequence number 24: antisense primer for SNP012: CCTCACTGTCAGAGATTCTGGGTCAGATAAATCCAAGA
Sequence number 25: sense primer for SNP013: CTAGTTTGTAAGCTTGGTTCTACAGTGAAAACATTGAGTA
Sequence number 26: antisense primer for SNP013: GTTTGGCTGTGAGTAAGGGATAGAGAGATGGTACAGAAA
SEQ ID NO: 27: sense primer for SNP014: CTAGTTTGTAAGCTTGGTTCTACAGTGAAAACATTGAGTA
Sequence number 28: antisense primer for SNP014: GTTTGGCTGTGAGTAAGGGATAGAGAGATGGTACAGAAA
SEQ ID NO: 29: sense primer for SNP015: GCCAGGCCTAAATTCTATTTTTAATAACTAATACGAAAGTGAA
Sequence number 30: antisense primer for SNP015: GCTTGTTCTACAGAAGATCATTAATGTTTTGTGACTATAT
Sequence number 31: sense primer for SNP016: GTGCTCTACCCAACTGCTAGTATCTAAGGTGCAAGA
Sequence number 32: antisense primer for SNP016: CCTTCCTTCTGCTTGAGGAGAGGAGAGGAAAGAATAA
Sequence number 33: sense primer for SNP017: CTTTGTTGGAATCATGTATAGAACATGCCTCTGAGTGCTAA
Sequence number 34: antisense primer for SNP017: TTTCAGAAGTCTGGGTAATTCAGTCTAGAGAATAGCTATA
Sequence number 35: sense primer for SNP018: TGCCAAACAAGCTAACGCGAAGTCTGTTCTCTGCAA
Sequence number 36: antisense primer for SNP018: GCACAGGTAGATTCTGCTTTCTAAAAATTTCACCTTTCTCTA
SEQ ID NO: 37: sense primer for SNP019: TGCCAAACAAGCTAACGCGAAGTCTGTTCTCTGCAA
Sequence number 38: antisense primer for SNP019: GCACAGGTAGATTCTGCTTTCTAAAAATTTCACCTTTCTCTA
Sequence number 39: sense primer for SNP020: GGCTTTCTTAGCATTGCTTGACAGAGACTGAGATTAGAAA
Sequence number 40: antisense primer for SNP020: AGGGACTTGAGAGAACAAAAATGGCTAAGGGAAAATTTTA
SEQ ID NO: 41: sense primer for SNP021: ATGAGATGCAGTCAGGTGTTACTAGTGTCTTCAATTATAT
Sequence number 42: antisense primer for SNP021: CACAGGAAACTTCCCTATACTGGCAGATACACTTGTGA
Sequence number 43: sense primer for SNP022: AAGACAACTTGGTTTTGTTTAGATGCTTTGCCACTAGAAA
Sequence number 44: antisense primer for SNP022: ATTGAATGTCCTACCTTGTACTTTCTGCAATGCCTATCAAA
Sequence number 45: sense primer for SNP023: TGCATTAGGAAAAGGACTGTGTACTTTGCTGAAATTGGTA
Sequence number 46: antisense primer for SNP023: TCTGAAAATGGAAAACAGAACGGTAATTGTCTCCATCAAA
SEQ ID NO: 47: sense primer for SNP024: CTGGACAATCTTTGACCTGACATGGACATCTTCTCAAA
Sequence number 48: antisense primer for SNP024: CATAAGCAGCCATTAGTGTTGGGGTTCTGACTACAAA
SEQ ID NO: 49: sense primer for SNP025: CTTAAGTTTCTACATTTCAAGCAGCACAAACCATGGACTA
Sequence number 50: antisense primer for SNP025: GGTTGAATTGACATTACTGTGGGTAAGTAAGAAGCATCTTTA
Sequence number 51: sense primer for SNP026: GCAGATGAACCTGGACCTGCCGTAAAACTCATGAA
Sequence number 52: antisense primer for SNP026: TGCACCCAAGTTCTTTCAGTGATCGACACTTGCGA
SEQ ID NO: 53: sense primer for SNP027: GTGATGGAGGTAATACTTGCCAATCATCCTTCTTTCTGAA
Sequence number 54: antisense primer for SNP027: AGCAGATTTCTTTTTTTCTTTTGGACCTTCAAGGTGTCTA
Sequence number 55: sense primer for SNP028: GCTTCACCTCTCTAGGGACCTAGAAAATGCTTCCTAA
Sequence number 56: antisense primer for SNP028: ATTGATTATTTCAGCTTGTCCTCACATACACTTTCATATA
SEQ ID NO: 57: sense primer for SNP029: CAAACAAACAAAAAAACCCAACATCCAAGGGTGTCAA
Sequence number 58: antisense primer for SNP029: TGGGGTTGCTTGATCCAGACTTTTCTCAGAAACACA
Sequence number 59: sense primer for SNP030: CTCTATCTTCAACAAAAACTATGGAGTGGTTCCAGCCTAA
Sequence number 60: antisense primer for SNP030: CTCACTTTTGGAATAGGAATGTCTGTCTTATGCCGTATCA
Sequence number 61: sense primer for SNP031: CCAGGCTTTTTTGTGAGTTTTGAGCATTATATTCACATTA
Sequence number 62: antisense primer for SNP031: AAGAAAAAGACTCTGAGAAATGATTTTCTTTTCTTGAAAA
Sequence number 63: sense primer for SNP032: TGTCCTGTCTTGCCATAAATGAAGCCCTTCTTATTGAATA
Sequence number 64: antisense primer for SNP032: GAAGTGAAAATGAAGATTCAACGTTCCTCTAGAGTGGGAA
Sequence number 65: sense primer for SNP033: CTTTGCTTGTGGACATCCAGATGGAAATTGGTTTTATA
Sequence number 66: antisense primer for SNP033: AAAAAAGGCAATAAATGTCTTTTAGTTCCAATCCTAATTA
Sequence number 67: sense primer for SNP034: AGGGCTCTAAAGAGCATTTGGTTGGTTCCAAAAATAAAAA
Sequence number 68: antisense primer for SNP034: CCCGTAGGCACCAGGGAAAAGCATTTTCTTGTTCA
Sequence number 69: sense primer for SNP035: TCCTTGATTGCAGGTATGCAAGTGGACAGTGATATCTA
Sequence number 70: antisense primer for SNP035: GGCCTTTGATGCTTGTAAAATCAATATTTTCTCATAGTATAT
Sequence number 71: sense primer for SNP036: AGGTTTTTTCTTGGAAGTTAAGTATCCTCTACTTTTTCGCTA
Sequence number 72: antisense primer for SNP036: CTTAAATTCCCATGGTCAGCCAAAACAGTGCTTAAAACTAA
Sequence number 73: sense primer for SNP037: ATTTTGCCTGTATGACTTGGAGTTCACATCATTAAGAATA
Sequence number 74: antisense primer for SNP037: ATGTCTTTATCTCAACGAAAGCAAGACCATTAAATGAAAAGAA
Sequence number 75: sense primer for SNP038: ATTACCTGCAACAGAAGTCAGCACATTCTTTCTATGAAGAA
Sequence number 76: antisense primer for SNP038: AGCACTTTTTTTAGTTACTAAGCCTTTTATTCAGATAGCACACTA
SEQ ID NO: 77: sense primer for SNP039: ACTCACATGTTGGTTCACCATATAAAATCAGCAAAAATGTCA
Sequence number 78: antisense primer for SNP039: GTGTGATTTTTCTCTTTGGATCTACTTGTATGTTGAATTAATA
Sequence number 79: sense primer for SNP040: AGAACTACAATAACCAGAGACTTTCATGACCAAGAATTTG
Sequence number 80: antisense primer for SNP040: ATCTTTTAGCTGCTTATTAAAGTTGTCATAGGCACAGAAA
Sequence number 81: sense primer for SNP041: ATAATACTTCACATTTTAACCTTCAAAGAGCTTTGCTTTTA
Sequence number 82: antisense primer for SNP041: AGATGATGGAAATCAAGGAGGCATAAAGATGGCTAAATTA
Sequence number 83: sense primer for SNP042: CATAGGCACTTCGACCAGTCCTACCGTAATATTCAAACA
Sequence number 84: antisense primer for SNP042: AGGGATGGCAACTAAATAAAAGTACCCTAAGCGTTTCTAAA
Sequence number 85: sense primer for SNP043: GGCATCATCTCATTTGTTGAGGGCCTGAATAAAACAAAAA
Sequence number 86: antisense primer for SNP043: AGATAAAGTAAATATTTTCACGGTCGTTAGGATACTTGAAA
Sequence number 87: sense primer for SNP044: ATGTTGCTTATGAATAAAAAAAACCCCAATAAAACTTGCATA
Sequence number 88: antisense primer for SNP044: ACACTGGATTTTCTTTCTCAAAAATGACCTCTTAGGTTCTTA
Sequence number 89: sense primer for SNP045: TTAAACTGGCAGATGAACCTGGACCTGCCGTAAAA
Sequence number 90: antisense primer for SNP045: TCTTTCAGTGATCGACACTTGCGACTTAGGTTGAGATA
Sequence number 91: sense primer for SNP046: AGAAGCCCGAGGAATGAGGCTAAGGGAGAAGAGGA
Sequence number 92: antisense primer for SNP046: ATTCAGGCACCTCTAGCGTGCTTGCCCCTTGAAAA
Sequence number 93: sense primer for SNP047: CTTCCTGTACAGCCTGTGGAACTCTGAGCCAATTA
Sequence number 94: antisense primer for SNP047: AGGGACTATTCTTGTGAGTCTTTTTGTATTGTTCAGTTTATTA
SEQ ID NO: 95: sense primer for SNP048: CTCTGAAACCAAAGAAAAGTCATTTAAAATCTCCCAAATA
Sequence number 96: antisense primer for SNP048: GTTTGTAATTGACATTATCTCCAATCCCTCAAATAGTCGTA
Sequence number 97: sense primer for SNP049: TAATCTCAAGTACCCAGGGACACAAACACTGCGGAA
SEQ ID NO: 98: antisense primer for SNP049: GGTAAAAGGGATGGGGCCCAAAGATTTGCATTTCT
SEQ ID NO: 99: sense primer for SNP050: AAAAGTCCCACACCTGTTCCTGATAAAGACTCTCACAA
Sequence number 100: antisense primer for SNP050: TCAAACTACCGACCTCCAAACCGCAAGGTACACTT
Sequence number 101: sense primer for SNP051: CAGCATGCCATTCAGTATCTTTTCTTACACAACAGTTATT
Sequence number 102: antisense primer for SNP051: TTGACAACACTGTGTGACAGTCTTCTGGTACCCAGA
SEQ ID NO: 103: sense primer for SNP052: GAGTTTCTGGGACGATGGATATTTGCGTTCCTCTT
Sequence number 104: antisense primer for SNP052: TAGCCCAGTGCTGGCTGTGGTCAATACTCAGAGGT
Sequence number 105: sense primer for SNP053: CAAAATGATCCTTTTCTTGAATTCTGTTCCTTAAAGTAACC
SEQ ID NO: 106: antisense primer for SNP053: TTAACTTTGGTGAGGCTCCACAGTCTACTGATTTCTG
SEQ ID NO: 107: sense primer for SNP054: TACAAGTGATCAAGTATTAAGAATGTATTCCCAGGGGAAGT
Sequence number 108: antisense primer for SNP054: ACTTTGCATTGTTGTTTACAATCAAGTTCAGGAGAAAGAC
SEQ ID NO: 109: sense primer for SNP055: TTTTACCAATCATTATTCTGGAGGCCACAAGATTTGCAAC
Sequence number 110: antisense primer for SNP055: TATGAAGTAGAGGAGATGGACACTCAACACGGTGACAACT
Sequence number 111: sense primer for SNP056: GTTCCAGTTGTCTGTGTCAAAAGGGAACAAAAGGAAGAA
Sequence number 112: antisense primer for SNP056: GTCTATCACAGAGATTGCCCACAGAGAACATGCAA
SEQ ID NO: 113: sense primer for SNP057: AGTTATCAAATAAATACCGAATTTGATGAATGAGAAAGAACAC
Sequence number 114: antisense primer for SNP057: AATCTATGGACAAGATATGAAAGTCTTCAGAGTCATAGAT
SEQ ID NO: 115: sense primer for SNP058: GTATTTTTTATGCCCCAATTTTTTTCTTTTCTCTTTTTGGG
SEQ ID NO: 116: antisense primer for SNP058: AGTGTAACAAAGGTGCTAAAAGTCCAGTAAAAACTTTACCA
Sequence number 117: sense primer for SNP059: TTATAGATCTGCTTTTATTTCATTTTAAAGGTGTGGGTCT
Sequence number 118: antisense primer for SNP059: ATAGGAACAATTACCACAATTCAAATTAGGAGTACTTTTT
SEQ ID NO: 119: sense primer for SNP060: CTTGTCAAGCTTCACAAATGTTCTGTTGAAAATTTGACGA
Sequence number 120: antisense primer for SNP060: TGGAAAAAAGGCGTCAATTCAATCCTTTCCCACCA
Sequence number 121: sense primer for SNP061: TTTTAAGGGGAACATGTTATTTTAGAAAATTGCCATTACC
Sequence number 122: antisense primer for SNP061: CTAGTATATGTGACAGTGATGTTTGCTGTAAGGACTTAAAC
SEQ ID NO: 123: sense primer for SNP062: AGTAGGGAGAGAGATTCTTACATAAAATTAGGATCCCGAG
Sequence number 124: antisense primer for SNP062: GGGAGATTCTTAGTGTATGTCTTCTCAATATTGCTTTCTCC
SEQ ID NO: 125: sense primer for SNP063: CCCCTGCAGCCACTTAATTTATATTTAAGTCACTTAAGAA
SEQ ID NO: 126: antisense primer for SNP063: GTCTCTTGGTGTGGGCTATTCTATGCTGCATCACA
SEQ ID NO: 127: sense primer for SNP064: TCCAAAGCCTGCAGTGACTCCTCCAATTCATAAGC
Sequence number 128: antisense primer for SNP064: ATTGAAGTCACTAATTAACACGTCGTCTCTACTAGCCTCA
SEQ ID NO: 129: sense primer for SNP065: TTAAATTCATGAATCCATAAGATTAAACCACTTGAGAGTA
SEQ ID NO: 130: antisense primer for SNP065: AGTGATTTCTATAAGAGGGAAACAAACTGTGACATCTGCTATA
SEQ ID NO: 131: sense primer for SNP066: GAGCGTGCGAGGAAAGAGTAAGTCCTAAGGAGGTA
Sequence number 132: antisense primer for SNP066: GTCCTATACTCTGGGGACTCAGGAAGAAACTGACTCA
SEQ ID NO: 133: sense primer for SNP067: GCTTTGATCCTAACCCTTTTCAGTCTTCATCTTTCTAGAGTA
Sequence number 134: antisense primer for SNP067: GCATTTGATAACATTATAAATGGAAGTTTACATGAAGGAATATA
SEQ ID NO: 135: sense primer for SNP068: GCTAGAGGAGATGCTGTCACTTTTGTGAATGCATTCTTA
SEQ ID NO: 136: antisense primer for SNP068: TTTAAAAGCCACAAAGAAGAGACGCTCACCCAGAGA
SEQ ID NO: 137: sense primer for SNP069: GCTAGAGGAGATGCTGTCACTTTTGTGAATGCATTCTTA
SEQ ID NO: 138: antisense primer for SNP069: TTTAAAAGCCACAAAGAAGAGACGCTCACCCAGAGA
SEQ ID NO: 139: sense primer for SNP070: GCTAGAGGAGATGCTGTCACTTTTGTGAATGCATTCTTA
Sequence number 140: antisense primer for SNP070: TTTAAAAGCCACAAAGAAGAGACGCTCACCCAGAGA
Sequence number 141: sense primer for SNP071: CCTGGTTCTTGGTTCTAAGAAGATCAGAGAAAGACGAGA
SEQ ID NO: 142: antisense primer for SNP071: TTCTCTTGCCCCAAGCAACAGTCCTAATGTCTTCCAA
Sequence number 143: sense primer for SNP072: AATCCCAGGAATTTGGATGAATATGCCATGCTGGATA
Sequence number 144: antisense primer for SNP072: GTAATGCCTAAAGCTCTTATCCCTATGCCTAGAGCATA
SEQ ID NO: 145: sense primer for SNP073: ATAGGGCTTACTATGTGTTAAGCACTGTTGAAAGTATTTA
SEQ ID NO: 146: antisense primer for SNP073: CATGGGGATCCCTATGTAAGTGGAAACCCTGATCA
SEQ ID NO: 147: sense primer for SNP074: ATCTTAAGGACATCATTCAGTGAGTTTTGGAAAATATGTA
SEQ ID NO: 148: antisense primer for SNP074: AGCCAGTGATTTCATTCTTAAGTATTTATCCAGAAGAAATA
SEQ ID NO: 149: sense primer for SNP075: GACAAAGTTCAAAAGAGACCACAAAAGTACCAGAAGGTAA
Sequence number 150: antisense primer for SNP075: GCACTACTTTAATTCCCAAGTATAGGAAGAAGAAACAGACTTA
Sequence number 151: sense primer for SNP076: TTGCACTCATCTCTAAGTGGAAATCTGAAGACATGTTCTA
Sequence number 152: antisense primer for SNP076: GACAAAAGATAGCAAGTGTTGGCAAGGATGTAGAGAAAA
SEQ ID NO: 153: sense primer for SNP077: TTGCACTCATCTCTAAGTGGAAATCTGAAGACATGTTCTA
SEQ ID NO: 154: antisense primer for SNP077: GACAAAAGATAGCAAGTGTTGGCAAGGATGTAGAGAAAA
Sequence number 155: sense primer for SNP078: CACTATTAAGCAGACATTTCAGTTGGTAGAATCCATGTAGAA
SEQ ID NO: 156: antisense primer for SNP078: ACCATTTATCTTAGCAAACACGTAAAGTACTATATTTCTTTGCTA
SEQ ID NO: 157: sense primer for SNP079: TCACAACTTGTGAAATTCAGGCTGCTATAGGAGTGTCTA
SEQ ID NO: 158: antisense primer for SNP079: AGCTGTAAATGGACTAAGAAATGTGAGTTTCATTAGAAGGTA
SEQ ID NO: 159: sense primer for SNP080: GATATTTCATGAGCACTTTGCAAAGTCACTATGAGAAGCA
Sequence number 160: antisense primer for SNP080: TCAATTGTGTGAATTTGTAGTTCCCACATACAAGTGAGAA
Sequence number 161: sense primer for SNP081: CCTTGTACGGCTACAAGGTTTACCTGTTGTTTAGGTAA
Sequence number 162: antisense primer for SNP081: TGCATTTCCGTCCCACCATCTCACCTACTGAGAGTA
SEQ ID NO: 163: sense primer for SNP082: CCCTTATTCAAACCAAATCTACTGTAGAACTTCAGTATAAGAATA
Sequence number 164: antisense primer for SNP082: AGTGAGAGTAGCCCTAACAATGGATTCATGAGAAACATCA
Sequence number 165: sense primer for SNP083: TGGAGGAAAACACACCCCGGTCTCACATTAAAGAA
SEQ ID NO: 166: antisense primer for SNP083: CCACTGCTTATGGAAATAAAGCCCCTCCTGTAAAGAA
Sequence number 167: sense primer for SNP084: TCTACACTTCCAGATGGTGAGCCCATGACTTACTTAAA
Sequence number 168: antisense primer for SNP084: CCTTTTCTCTTTGAAGCCGACAGTTTGGCTTCTTTA
SEQ ID NO: 169: sense primer for SNP085: AGAGGAGGAAATTAAAGCTAGGAGAGTTTAAACAATGTGA
SEQ ID NO: 170: antisense primer for SNP085: CATAATTAATTTCCAAACATTTTTTACACACAATTTTACACATA
Sequence number 171: sense primer for SNP086: CAAAGCATTGTTATGCAGATTAAATGAACTAATATGTGTA
Sequence number 172: antisense primer for SNP086: ATGAATGAAGAGACAGAGAAAATGAAAACGAGATATAAATA
SEQ ID NO: 173: sense primer for SNP087: AGGCTGTTACAAGGATCAACTCAGATACTGCATGAAAA
SEQ ID NO: 174: antisense primer for SNP087: TGTCTTACATGACGGCAGACAAGAGAGAATGAGAACTA
SEQ ID NO: 175: sense primer for SNP088: CGGGAACAAGGAGATCAATTCCCTTAGAAGACCAA
SEQ ID NO: 176: antisense primer for SNP088: CCACAATTGTAGCCACTTCCTTGGAGGCTTTCATTA
Sequence number 177: sense primer for SNP089: ATTCACTCAACACATACTTTCTGAGAGCCTACTCTGAGTTA
Sequence number 178: antisense primer for SNP089: GGTGAATCCAAATAAAGTTTGTAAGTTAGTTCATGGTATTA
SEQ ID NO: 179: sense primer for SNP090: GCTGCTAATTGTATACCATTCAGTTCCTGGTCTTTATATCAAA
Sequence number 180: antisense primer for SNP090: TTCAAAAGAGAGTAAGCAACTTACCCAATGTCATCCAGCTA
SEQ ID NO: 181: sense primer for SNP091: GGGCCTTGTCTCTCATTTCTGGTCCAATTAATTTCTTAAA
Sequence number 182: antisense primer for SNP091: TCCCACTTGGGCGGAGTCTCAAGTTCTCATTCTGA
SEQ ID NO: 183: sense primer for SNP092: GGGCCTTGTCTCTCATTTCTGGTCCAATTAATTTCTTAAA
SEQ ID NO: 184: antisense primer for SNP092: TCCCACTTGGGCGGAGTCTCAAGTTCTCATTCTGA
Sequence number 185: sense primer for SNP093: CCAGCTCTCTGGGAGGTAGTTAGTAGGAATGCTTA
SEQ ID NO: 186: antisense primer for SNP093: GAGCCTGGGCATCAAGTGCACAGGAAGACAGTTAA
SEQ ID NO: 187: sense primer for SNP094: CCAGCTCTCTGGGAGGTAGTTAGTAGGAATGCTTA
SEQ ID NO: 188: antisense primer for SNP094: GAGCCTGGGCATCAAGTGCACAGGAAGACAGTTAA
Sequence number 189: sense primer for SNP095: TAAGGCACATACACTTTGAGTAAACTCCGGGGTGATATTA
Sequence number 190: antisense primer for SNP095: GAGCCAGACCTCGTCTCAAAGAAAGAAAAAAAAGGAGAAA
Sequence number 191: sense primer for SNP096: GAAATACAACAAACACCCACACGCGAGCCAACGGAAA
SEQ ID NO: 192: antisense primer for SNP096: ACAACTTCCCAGGTTAGCCATTATTATCACCCCATTTTAAA
SEQ ID NO: 193: query probe 1 for SNP001: TGAGAGGAGAACTTGTGG
SEQ ID NO: 194: query probe 2 for SNP001: GTTGAGAGGAGAACTTGTGA
Sequence number 195: query probe 1 for SNP002: GAGTCTGCTGTCCTGG
SEQ ID NO: 196: query probe 2 for SNP002: GGAGTCTGCTGTCCTGA
SEQ ID NO: 197: query probe 1 for SNP003: CTGAGGTCTTTTTCAAATCTATG
SEQ ID NO: 198: query probe 2 for SNP003: ATCTCTGAGGTCTTTTTCAAATCTATA
SEQ ID NO: 199: query probe 1 for SNP004: CCAAAGAAGGTTTTATCTTCTTA
SEQ ID NO: 200: query probe 2 for SNP004: CCAAAGAAGGTTTTATCTTCTTT
Sequence number 201: query probe 1 for SNP005: GAGCTGGGAACTGATTTTTA
Sequence number 202: query probe 2 for SNP005: AGCTGGGAACTGATTTTTT
Sequence number 203: query probe 1 for SNP006: AGAGAAGTAAATAATGGATAGCG
Sequence number 204: query probe 2 for SNP006: GAGAGAAGTAAATAATGGATAGCA
Sequence number 205: query probe 1 for SNP007: CAATGGCATCTGGCC
Sequence number 206: query probe 2 for SNP007: GCAATGGCATCTGGCT
SEQ ID NO: 207: query probe 1 for SNP008: ATGGCTAAGTGGGACTTC
Sequence number 208: query probe 2 for SNP008: CATGGCTAAGTGGGACTTT
Sequence number 209: query probe 1 for SNP009: AGAGGTTTCTACTACCATCG
Sequence number 210: query probe 2 for SNP009: CAAGAGGTTTCTACTACCATCA
Sequence number 211: query probe 1 for SNP010: CTGTAGTATCCCCAAGATC
SEQ ID NO: 212: query probe 2 for SNP010: CTGTAGTATCCCCAAGATT
Sequence number 213: query probe 1 for SNP011: ACTACTTTCGTAATGACACAAAG
Sequence number 214: query probe 2 for SNP011: ACTACTTTCGTAATGACACAAAT
Sequence number 215: query probe 1 for SNP012: GATGTCATTAACCTCCTAACC
Sequence number 216: query probe 2 for SNP012: GGATGTCATTAACCTCCTAACA
Sequence number 217: query probe 1 for SNP013: CATGGGATGGAATTCAGC
Sequence number 218: query probe 2 for SNP013: CATGGGATGGAATTCAGT
Sequence number 219: query probe 1 for SNP014: CTGCATTTCTTCTTCCG
Sequence number 220: query probe 2 for SNP014: CTCTGCATTTCTTCTTCCA
Sequence number 221: query probe 1 for SNP015: CAGATGCATGGTAAGAAATTAGA
Sequence number 222: query probe 2 for SNP015: AGATGCATGGTAAGAAATTAGG
Sequence number 223: query probe 1 for SNP016: CTTGAGTCCTGAATAAACATCA
Sequence number 224: query probe 2 for SNP016: CTTGAGTCCTGAATAAACATCG
Sequence number 225: query probe 1 for SNP017: AAGAAAATTATTTGTTCTTAGATGTTTTT
Sequence number 226: query probe 2 for SNP017: AAGAAAATTATTTGTTCTTAGATGTTTTC
Sequence number 227: query probe 1 for SNP018: TGGGCTGGGCTGTGAC
Sequence number 228: query probe 2 for SNP018: GGGCTGGGCTGTGAT
Sequence number 229: query probe 1 for SNP019: ACTTATTTAATCTTCAAAGCAATCG
Sequence number 230: query probe 2 for SNP019: ACTTATTTAATCTTCAAAGCAATCC
Sequence number 231: query probe 1 for SNP020: TCGAGTTAGAATGTGAGATGG
Sequence number 232: query probe 2 for SNP020: TCGAGTTAGAATGTGAGATGC
Sequence number 233: query probe 1 for SNP021: GCAGTCCTCCTTCTCC
Sequence number 234: query probe 2 for SNP021: GGCAGTCCTCCTTCTCT
Sequence number 235: query probe 1 for SNP022: CATTGCAAAATTCTAAGTCTTTG
Sequence number 236: query probe 2 for SNP022: GCATTGCAAAATTCTAAGTCTTTA
Sequence number 237: query probe 1 for SNP023: ACCTCTTATGTATCCTGAAAAGA
Sequence number 238: query probe 2 for SNP023: ACCTCTTATGTATCCTGAAAAGG
Sequence number 239: query probe 1 for SNP024: GTGGCTGCTCCATTGAATA
Sequence number 240: query probe 2 for SNP024: GGCTGCTCCATTGAATG
Sequence number 241: query probe 1 for SNP025: ATTGATTTGAACCCAAAACG
Sequence number 242: query probe 2 for SNP025: AAATTGATTTGAACCCAAAACA
Sequence number 243: query probe 1 for SNP026: AGAGGTTCAATTATAGTAGTCAC
Sequence number 244: query probe 2 for SNP026: GTAGAGGTTCAATTATAGTAGTCAT
Sequence number 245: query probe 1 for SNP027: CTCCTGGGCAACTTTCT
Sequence number 246: query probe 2 for SNP027: TCCTGGGCAACTTTCG
Sequence number 247: query probe 1 for SNP028: CATCTTAATTCTTTGATGGGCT
Sequence number 248: query probe 2 for SNP028: CTTAATTCTTTGATGGGCC
Sequence number 249: query probe 1 for SNP029: GCTGTGAACTGTTTGTCCA
Sequence number 250: query probe 2 for SNP029: CTGTGAACTGTTTGTCCG
Sequence number 251: query probe 1 for SNP030: CCCTGCCCTCCAAAAC
Sequence number 252: query probe 2 for SNP030: CCCTGCCCTCCAAAAA
Sequence number 253: query probe 1 for SNP031: GTGTCATGCGATGAATTAAAAC
Sequence number 254: query probe 2 for SNP031: GTGTCATGCGATGAATTAAAAT
Sequence number 255: query probe 1 for SNP032: CACCGCGGAGAGTAG
Sequence number 256: query probe 2 for SNP032: GCACCGCGGAGAGTAA
Sequence number 257: query probe 1 for SNP033: CCCCTCATTGGCTTCTA
Sequence number 258: query probe 2 for SNP033: CCCTCATTGGCTTCTG
Sequence number 259: query probe 1 for SNP034: AAAAAAGAAAAGTCGACCAT
Sequence number 260: query probe 2 for SNP034: AAAAAGAAAAGTCGACCAC
Sequence number 261: query probe 1 for SNP035: CGGAACAGGTTTTACACAAT
Sequence number 262: query probe 2 for SNP035: CGGAACAGGTTTTACACAAG
Sequence number 263: query probe 1 for SNP036: CAAAATTCCAACTCTTGTACC
Sequence number 264: query probe 2 for SNP036: ACAAAATTCCAACTCTTGTACA
Sequence number 265: query probe 1 for SNP037: CATTTGCCTTTTTTACAGTTG
Sequence number 266: query probe 2 for SNP037: CATTTGCCTTTTTTACAGTTC
Sequence number 267: query probe 1 for SNP038: GTGTGTATTGGGTATAAAAATAAGC
Sequence number 268: query probe 2 for SNP038: GTGTGTATTGGGTATAAAAATAAGT
Sequence number 269: query probe 1 for SNP039: GAAAAGGAGCATTCACACC
Sequence number 270: query probe 2 for SNP039: CAGAAAAGGAGCATTCACACA
Sequence number 271: query probe 1 for SNP040: ACAACTCAAATGACTGATGG
Sequence number 272: query probe 2 for SNP040: GAACAACTCAAATGACTGATGA
SEQ ID NO: 273: query probe 1 for SNP041: CAGGGATCTGAGCTGTG
Sequence number 274: query probe 2 for SNP041: CCAGGGATCTGAGCTGTA
Sequence number 275: query probe 1 for SNP042: GGATGGCAGCTCACG
Sequence number 276: query probe 2 for SNP042: AGGATGGCAGCTCACA
Sequence number 277: query probe 1 for SNP043: TGACCTATACCATCAGCTT
Sequence number 278: query probe 2 for SNP043: TGACCTATACCATCAGCTC
Sequence number 279: query probe 1 for SNP044: ACAATAGATATAATTTCTACGGCTA
Sequence number 280: query probe 2 for SNP044: ACAATAGATATAATTTCTACGGCTG
Sequence number 281: query probe 1 for SNP045: GTATGTGTTGTGTGTGTATG
SEQ ID NO: 282: query probe 2 for SNP045: ATGTATGTGTTGTGTGTGTATA
SEQ ID NO: 283: query probe 1 for SNP046: GCACACGTGAGGGT
Sequence number 284: query probe 2 for SNP046: GCACACGTGAGGGC
Sequence number 285: query probe 1 for SNP047: TGTCAATTCACTATCGACAC
SEQ ID NO: 286: query probe 2 for SNP047: TTGTCAATTCACTATCGACAT
Sequence number 287: query probe 1 for SNP048: CCTAACTTCATATGTTGAAACTT
Sequence number 288: query probe 2 for SNP048: CCTAACTTCATATGTTGAAACTC
Sequence number 289: query probe 1 for SNP049: AGTATTACTCTTCCAAAACAGC
Sequence number 290: query probe 2 for SNP049: TCTCTAGTATTACTCTTCCAAAACAGA
SEQ ID NO: 291: query probe 1 for SNP050: ATCTGTGTTAGGTTCCAG
Sequence number 292: query probe 2 for SNP050: CATCTGTGTTAGGTTCCAA
SEQ ID NO: 293: query probe 1 for SNP051: GCCTAGCTTGTAAATTGCTC
SEQ ID NO: 294: query probe 2 for SNP051: GCCTAGCTTGTAAATTGCTG
Sequence number 295: query probe 1 for SNP052: GGACTCCAGCCCAGG
Sequence number 296: query probe 2 for SNP052: TGGGACTCCAGCCCAGA
Sequence number 297: query probe 1 for SNP053: ACATTTTAGCTGTTGATCCT
Sequence number 298: query probe 2 for SNP053: ACATTTTAGCTGTTGATCCC
Sequence number 299: query probe 1 for SNP054: ACTTTAATTCCATGCACCAT
Sequence number 300: query probe 2 for SNP054: ACTTTAATTCCATGCACCAG
Sequence number 301: query probe 1 for SNP055: CCCCACCCACTCTCATT
Sequence number 302: query probe 2 for SNP055: CCCACCCACTCTCATC
SEQ ID NO: 303: query probe 1 for SNP056: GGGAGAATACCAACGTAGTA
Sequence number 304: query probe 2 for SNP056: GGGAGAATACCAACGTAGTG
Sequence number 305: query probe 1 for SNP057: CAATAAATGTTTATGAGCAAACG
SEQ ID NO: 306: query probe 2 for SNP057: GTCAATAAATGTTTATGAGCAAACA
SEQ ID NO: 307: query probe 1 for SNP058: AACCAAGGAAGGTGAGTATGAA
SEQ ID NO: 308: query probe 2 for SNP058: CCAAGGAAGGTGAGTATGAG
Sequence number 309: query probe 1 for SNP059: AGTGTGGAAGTGGGG
SEQ ID NO: 310: query probe 2 for SNP059: CCAGAGTGTGGAAGTGGGA
SEQ ID NO: 311: query probe 1 for SNP060: CCACAGATATTTATTACATGTCAC
SEQ ID NO: 312: query probe 2 for SNP060: ACTCCACAGATATTTATTACATGTCAA
Sequence number 313: query probe 1 for SNP061: ACCTGTGTCTGTGAAGAGTA
SEQ ID NO: 314: query probe 2 for SNP061: CCTGTGTCTGTGAAGAGTG
Sequence number 315: query probe 1 for SNP062: ATGGTGTTTGTGATACACTG
Sequence number 316: query probe 2 for SNP062: AATGGTGTTTGTGATACACTA
SEQ ID NO: 317: query probe 1 for SNP063: TTCCCCATGAATGACTTTTC
Sequence number 318: query probe 2 for SNP063: TTCCCCATGAATGACTTTTT
Sequence number 319: query probe 1 for SNP064: TCTGAGCAATAAAAACATTAATCAG
Sequence number 320: query probe 2 for SNP064: CTGAGCAATAAAAACATTAATCAC
Sequence number 321: query probe 1 for SNP065: TTGTTCGTTATACAAAAAGTAAAACAAT
Sequence number 322: query probe 2 for SNP065: TTGTTCGTTATACAAAAAGTAAAACAAC
Sequence number 323: query probe 1 for SNP066: GTTGCAGCCTGCCC
Sequence number 324: query probe 2 for SNP066: AGTTGCAGCCTGCCT
Sequence number 325: query probe 1 for SNP067: ATCCCCTTTTAACCTTTGG
Sequence number 326: query probe 2 for SNP067: CCCCTTTTAACCTTTGC
SEQ ID NO: 327: query probe 1 for SNP068: TTGGCTGACTTTTGGAGGG
Sequence number 328: query probe 2 for SNP068: TGGCTGACTTTTGGAGGA
Sequence number 329: query probe 1 for SNP069: CATCCTTGCTTGTGAAGTAA
Sequence number 330: query probe 2 for SNP069: ATCCTTGCTTGTGAAGTAG
Sequence number 331: query probe 1 for SNP070: TGCAACCTGATTAGTAGAAACC
Sequence number 332: query probe 2 for SNP070: TGCAACCTGATTAGTAGAAACT
Sequence number 333: query probe 1 for SNP071: ATTTTATTCACAAAAGGGCG
Sequence number 334: query probe 2 for SNP071: CCATTTTATTCACAAAAGGGCA
Sequence number 335: query probe 1 for SNP072: CCCAGCACCCTATACACA
Sequence number 336: query probe 2 for SNP072: CCAGCACCCTATACACG
Sequence number 337: query probe 1 for SNP073: ATGGGTCCTTAAGAGATTG
SEQ ID NO: 338: query probe 2 for SNP073: AGATGGGTCCTTAAGAGATTA
Sequence number 339: query probe 1 for SNP074: ATATTCATCCATATATTGTTGCAT
Sequence number 340: query probe 2 for SNP074: ATATTCATCCATATATTGTTGCAC
Sequence number 341: query probe 1 for SNP075: CTGGATGGTTGGAATGTTC
Sequence number 342: query probe 2 for SNP075: ACTGGATGGTTGGAATGTTT
Sequence number 343: query probe 1 for SNP076: CAAGGAACATCCGTACAG
Sequence number 344: query probe 2 for SNP076: CAAGGAACATCCGTACAA
Sequence number 345: query probe 1 for SNP077: TGGACAGAGAATCCCCC
Sequence number 346: query probe 2 for SNP077: GGACAGAGAATCCCCT
SEQ ID NO: 347: query probe 1 for SNP078: ATGCAAGATTTTTCAGCGTAT
Sequence number 348: query probe 2 for SNP078: GCAAGATTTTTCAGCGTAC
Sequence number 349: query probe 1 for SNP079: CCAGACATGGCCTTTGA
SEQ ID NO: 350: query probe 2 for SNP079: CAGACATGGCCTTTGG
Sequence number 351: query probe 1 for SNP080: AAATTTCTCTTGAGTACACAATG
Sequence number 352: query probe 2 for SNP080: CCAAATTTCTCTTGAGTACACAATA
Sequence number 353: query probe 1 for SNP081: ATGGTCTCAGGAAAAGTTC
Sequence number 354: query probe 2 for SNP081: GATGGTCTCAGGAAAAGTTA
Sequence number 355: query probe 1 for SNP082: ATTGGTCTTCATCAAGCTT
Sequence number 356: query probe 2 for SNP082: ATTGGTCTTCATCAAGCTC
Sequence number 357: query probe 1 for SNP083: CTTTCTTCACCACAGTGATTCATA
Sequence number 358: query probe 2 for SNP083: TCTTCACCACAGTGATTCATG
Sequence number 359: query probe 1 for SNP084: TGAGGGTTGGCCTCTTTT
Sequence number 360: query probe 2 for SNP084: AGGGTTGGCCTCTTTC
Sequence number 361: query probe 1 for SNP085: TGCCCTGAATTTCTGGG
Sequence number 362: query probe 2 for SNP085: AACTGCCCTGAATTTCTGGA
SEQ ID NO: 363: query probe 1 for SNP086: CCAGGCTTAGCTTACTTTG
Sequence number 364: query probe 2 for SNP086: GCCAGGCTTAGCTTACTTTA
Sequence number 365: query probe 1 for SNP087: CAGAAAGCTGGACTCATCAA
Sequence number 366: query probe 2 for SNP087: GAAAGCTGGACTCATCAG
Sequence number 367: query probe 1 for SNP088: GAGCAAATTCAGCCAGATA
Sequence number 368: query probe 2 for SNP088: AGCAAATTCAGCCAGATG
Sequence number 369: query probe 1 for SNP089: ATCTTAAATCTTACATCCAAAGAG
Sequence number 370: query probe 2 for SNP089: AATCTTAAATCTTACATCCAAAGAA
SEQ ID NO: 371: query probe 1 for SNP090: TCAAGTTGTTATGTCAGATGG
Sequence number 372: query probe 2 for SNP090: GTCAAGTTGTTATGTCAGATGA
SEQ ID NO: 373: query probe 1 for SNP091: CCCCCTTGCCGCC
Sequence number 374: query probe 2 for SNP091: ACCCCCTTGCCGCT
Sequence number 375: query probe 1 for SNP092: AGATACATGAGAACCCCAG
Sequence number 376: query probe 2 for SNP092: AGATACATGAGAACCCCAT
SEQ ID NO: 377: query probe 1 for SNP093: CCTGGCTGATCCTCTGT
Sequence number 378: query probe 2 for SNP093: CTGGCTGATCCTCTGC
SEQ ID NO: 379: query probe 1 for SNP094: CCATTGTCAAAACTTGAAATAACA
SEQ ID NO: 380: query probe 2 for SNP094: CCATTGTCAAAACTTGAAATAACT
SEQ ID NO: 381: query probe 1 for SNP095: CTCAGTGTCTTCCCACAATA
Sequence number 382: query probe 2 for SNP095: CAGTGTCTTCCCACAATG
SEQ ID NO: 383: query probe 1 for SNP096: GGTCTTGAGCCCAATCC
Sequence number 384: query probe 2 for SNP096: GGTCTTGAGCCCAATCT
SEQ ID NO: 385: common probe for SNP001: TAAATGAGAAAGGGGAGAGAAAAACTTCAGACAACT
Sequence number 386: common probe for SNP002: GCTCCAGGCCCGGGTCTGCC
Sequence number 387: common probe for SNP003: ATTATGTGGCCTTTTGTTCATTGACTTCCATGT
SEQ ID NO: 388: common probe for SNP004: TGTGTAATCCACCAAAGAGATGTCACTGACGTT
Sequence number 389: common probe for SNP005: AAGTGCTGTGTGGGAGTTTGTCTCACA
Sequence number 390: common probe for SNP006: AGACTGGGATAAGTTAGGACTTTGAATGCCA
Sequence number 391: common probe for SNP007: ATGAACGCTGCTGCCTGAATCACAGT
SEQ ID NO: 392: common probe for SNP008: AGTGACTCAAACCCTGTGTTCAGATGAAGC
SEQ ID NO: 393: common probe for SNP009: CAATATGGGGAATAACTCCAGCTAGCCTCAG
SEQ ID NO: 394: common probe for SNP010: CTTTCCAACCCAAAGTCTATAATCCTTCTAGGCATT
SEQ ID NO: 395: common probe for SNP011: ATGTTATCTGGCTTTTTCACTCTCATTCTTTCACAAG
Sequence number 396: common probe for SNP012: GTGAAGAAAGAGCTCACTTTTGGTTCCATCTGAG
SEQ ID NO: 397: common probe for SNP013: GCCCAAGAGGAGAGTTGGCCTTCA
Sequence number 398: common probe for SNP014: TATATACTATCTCTCCCCCTTGCTCTTATAAAACA
SEQ ID NO: 399: common probe for SNP015: ACAAACTGGAGATGGGCCATGGAC
Sequence number 400: common probe for SNP016: GTGATGTCCAGGTACTACTTTGAGGGCC
Sequence number 401: common probe for SNP017: CTTCAATCAACCACTCAAGGGAGTTTAGAAGAG
SEQ ID NO: 402: common probe for SNP018: TACCCAGTGCTAAATAAGATTGGTAGGGTTCCT
Sequence number 403: common probe for SNP019: AACGAAATAGGCATCATTGAGCCAGGC
SEQ ID NO: 404: common probe for SNP020: CAAAAAAATTGCTTAGTTAACACACAGTTGGGTTGC
SEQ ID NO: 405: common probe for SNP021: AGGTTACATGAGGCAGGAATAAGAAGTCAGACAGAGAC
SEQ ID NO: 406: common probe for SNP022: TTCAAAGTTTCCCATTCAAGACCCATGTTTTCT
Sequence number 407: common probe for SNP023: GCTCCATTCAAGAAGTCATGGGCCTACC
Sequence number 408: common probe for SNP024: GGCCGTTGGCTGCCTACCGTC
SEQ ID NO: 409: common probe for SNP025: AACTTTCTAAAATTGCTGCCATACTTTTGCATTTTGAAC
Sequence number 410: common probe for SNP026: ATACACACACAACACATACATACACAAGACACAACAC
Sequence number 411: common probe for SNP027: GTCATGGGTGGAGCTATAGGGCTGG
Sequence number 412: common probe for SNP028: GCAGCCCTTTCTCCTCTAGCTGG
SEQ ID NO: 413: common probe for SNP029: CTGGGAAGGCCAGAGAGGGAGAC
Sequence number 414: common probe for SNP030: CTCATGTCCTTATCACATACAAATACATTCATTCCAACCC
Sequence number 415: common probe for SNP031: AGGGCTGTGTTAAAATAGTGACTGAATTGTCAGG
Sequence number 416: common probe for SNP032: GACGCACGTTCGCATCATCGC
Sequence number 417: common probe for SNP033: TCATGAGCAAATACCCTTGCTATAGACAACTTTTCCT
Sequence number 418: common probe for SNP034: ATTATTACTTTCTAGTCACATTTTTATTCAGGCCCAC
SEQ ID NO: 419: common probe for SNP035: ACCTATGGAGATAAAAGATTTTGAATCCCTGTGT
SEQ ID NO: 420: common probe for SNP036: TTTCACCGAGGTCACTCCAGGTTCTAAATTTGTGAAA
Sequence number 421: common probe for SNP037: CAAGAGTACTTTTTTTTTTTATTTCAGCTTTTCATGC
Sequence number 422: common probe for SNP038: GCTTTAATTAATTTGAAAATCCCTATTCACCAAA
Sequence number 423: common probe for SNP039: GCTTCTCTTGTCATGAAAAATCAACATGAAAACAGCAAA
Sequence number 424: common probe for SNP040: AAGAGGAACTGTAGGATGAAGAGTTTCCTAAAACC
SEQ ID NO: 425: common probe for SNP041: ACCTGCCTTTGGCCTCAAATGG
Sequence number 426: common probe for SNP042: CCCCCATGGACACTGTTTGTGTAGC
SEQ ID NO: 427: common probe for SNP043: CCATGGTTCTTAAGCCTCTGGACTCT
Sequence number 428: common probe for SNP044: TTCAAATTCACCTTAAAATGCGCCAGG
SEQ ID NO: 429: common probe for SNP045: TGACTACTATAATTGAACCTCTACTGTCTCAGGCAC
Sequence number 430: common probe for SNP046: TCAAAAGCGTCACTCCCAGTTTTGGAGC
Sequence number 431: common probe for SNP047: TACCCCTTCTAAGGTCTCCTCTGCTTTGAAGAAGA
Sequence number 432: common probe for SNP048: CACTCCCCAATGTAATGATATTAGGATGTG
Sequence number 433: common probe for SNP049: GGTTCTCAAAGTGTATTCCCCAGACC
Sequence number 434: common probe for SNP050: TTGCTGCTGGGATAGGTCACCGC
SEQ ID NO: 435: common probe for SNP051: TATAAACACATCCCTGAATGTTTTCCTTTTCCTCTGT
Sequence number 436: common probe for SNP052: CTACCATATTCCAGAGCCCACGCTCA
SEQ ID NO: 437: common probe for SNP053: GATGAACCTGTCCATGGAGCTCCAT
SEQ ID NO: 438: common probe for SNP054: GTATTCCAGACATCTCCAGCCTGTGTGC
SEQ ID NO: 439: common probe for SNP055: ACTCTCTAGCCCTCGATCTGCTCTTG
Sequence number 440: common probe for SNP056: GTAGTAGAGGAAGAGCTCTTCAAAGAAGGCCAA
Sequence number 441: common probe for SNP057: AAAGGTATCTAATAAGTACTGCATTGAACAGT
SEQ ID NO: 442: common probe for SNP058: GAGGGTATCCCAGAGAGGAGAGAGCT
SEQ ID NO: 443: common probe for SNP059: CCGTGTCTGTGTGCATGTGGGAG
Sequence number 444: common probe for SNP060: CTCCGTAAAAGAAATTGCCTTACCTGCA
Sequence number 445: common probe for SNP061: GAGGGTTCCATATTCAGACACAACATGGGAG
SEQ ID NO: 446: common probe for SNP062: AGAGAAGCTAATATATGTCTAATTGGTGTTGC
Sequence number 447: common probe for SNP063: CCCCCTCCTTTATAAAATTGACACCCATGC
Sequence number 448: common probe for SNP064: GTCATCTGAAAATTTCTCATCATCGATGTTAACTGAAC
SEQ ID NO: 449: common probe for SNP065: TGAAAGTTTCCTACAAAAATTTAAACTATGAGCA
SEQ ID NO: 450: common probe for SNP066: CATGGGATAATCGTGCCAGGGAAACAGAACAATTG
Sequence number 451: common probe for SNP067: CTTTGCATTTTGAAGGCATGTAACATGTAATCAGTCTT
Sequence number 452: common probe for SNP068: GACCCATTGAAAACATAGCATAACCCAATTCTGC
SEQ ID NO: 453: common probe for SNP069: TCATGGAATACTCTCCATCATCTCTTTTTCCCCCC
SEQ ID NO: 454: common probe for SNP070: TGCTCTTCCTGGCCTAGTGCAGTT
SEQ ID NO: 455: common probe for SNP071: CTAAGAGATGTTAAATGAGTCATCCAAGGCCATACAG
SEQ ID NO: 456: common probe for SNP072: CACCCAAGGGGAGAAATGGGAGGG
SEQ ID NO: 457: common probe for SNP073: TGATGAAGATTAAATGGGAACGTGCATGCAAAG
Sequence number 458: common probe for SNP074: GTATAGGCAGTTCCTTTTCTGCTGAATAGTATTCCA
SEQ ID NO: 459: common probe for SNP075: CCAGCTGGAGTGCCTCAGATCATAGTAAC
Sequence number 460: common probe for SNP076: TTTTCCATAATGGCTGTACTAATTTACATTCCCACCA
Sequence number 461: common probe for SNP077: CGGTTAATTCAATTCAACAAGAAATTATTGAGAG
Sequence number 462: common probe for SNP078: CATTTGAGAGGGTGCAGAAGCAACC
Sequence number 463: common probe for SNP079: AGCTCCCCATGTATTATTTTGGTTAATCCTCACA
Sequence number 464: common probe for SNP080: CCTCAGACTGTACTTTATGCCTAAGGAATAGCT
SEQ ID NO: 465: common probe for SNP081: TGTTTTTCATAAGGCTGTCTTTGGTCTTGAAAAGCC
Sequence number 466: common probe for SNP082: TGAAGCTGTGAAGACTATGTGTTCGGTCT
Sequence number 467: common probe for SNP083: CACAGAAGCGGAGGTACCCTGAGC
Sequence number 468: common probe for SNP084: TCCGTGGGCATAGCCGACATCAG
Sequence number 469: common probe for SNP085: CCATAGAAAATCTTCATAGTTTAGAGGTTGTTGAGCCT
Sequence number 470: common probe for SNP086: TTCATTAGTCTCACTCTAGTGTTACTATGGCCAACA
Sequence number 471: common probe for SNP087: CTTGACTTCTTCCCCATGCCTAATGTTCCC
SEQ ID NO: 472: common probe for SNP088: TTTACCCCTTCACTTTCTAGCCCCAGGG
Sequence number 473: common probe for SNP089: TCATGCTATATTCATTGCTAGTTGACAAATTTTTT
Sequence number 474: common probe for SNP090: TTCCCTGCCCCCTGTTTCATGG
SEQ ID NO: 475: common probe for SNP091: CCTTGAACAGGCCAACCATGGTCC
SEQ ID NO: 476: common probe for SNP092: AAGGTCATCCAGTAAAGTCCTAGGAGCTAGAG
SEQ ID NO: 477: common probe for SNP093: ACCTGAGGCACAAAGGTTCTATATAGGAGTG
Sequence number 478: common probe for SNP094: CCCAGGACAGGCCCTTAGCCC
SEQ ID NO: 479: common probe for SNP095: AGAAAGTGGGTGGTCCAGCCAG
Sequence number 480: common probe for SNP096: GTCTTACTCTTCATTTCACCCTCGATCAGTAGCT

Claims (4)

  A probe set for predicting the risk of developing primary biliary cirrhosis, comprising an oligonucleotide or polynucleotide that hybridizes with rs4979462 and an oligonucleotide or polynucleotide that hybridizes with rs4938534.   A primer set for predicting the risk of developing primary biliary cirrhosis, comprising an oligonucleotide or polynucleotide that hybridizes with rs4979462 and an oligonucleotide or polynucleotide that hybridizes with rs4938534. It characterized in that it comprises a primer set according to the probe set and / or claim 2 according to claim 1, risk prediction kit of primary biliary cirrhosis. (A) determining rs4979462 and rs4938534 using a sample collected from a human individual, and (b) risk of developing primary biliary cirrhosis in the human individual based on the genotype determined in step (a) A method for predicting the onset risk of primary biliary cirrhosis, characterized by comprising: