WO2019027005A1 - Method for evaluating tuberculosis onset risk specifically to genetic lineage of mycobacterium tuberculosis - Google Patents

Method for evaluating tuberculosis onset risk specifically to genetic lineage of mycobacterium tuberculosis Download PDF

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WO2019027005A1
WO2019027005A1 PCT/JP2018/029060 JP2018029060W WO2019027005A1 WO 2019027005 A1 WO2019027005 A1 WO 2019027005A1 JP 2018029060 W JP2018029060 W JP 2018029060W WO 2019027005 A1 WO2019027005 A1 WO 2019027005A1
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base
seq
tuberculosis
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徳永　勝士
陽輔 大前
理人 豊岡
英樹 野内
泰誠 莚田
充明 久保
スラカメ マハシリモンコン
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国立大学法人東京大学
国立研究開発法人理化学研究所
タイ国 ミニストリー オブ パブリック ヘルス、デパートメント オブ メディカル サイエンシス
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • C12Q1/6832—Enhancement of hybridisation reaction
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • 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
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    • 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

Definitions

  • the present invention relates to a method of determining the risk of developing tuberculosis.
  • Non-Patent Document 1 Identification of human gene polymorphisms associated with the onset of tuberculosis has been variously performed on the entire genome by candidate gene research and the like (see Non-Patent Document 1). On the other hand, researches on gene mutations associated with the onset of M. tuberculosis genome have also been conducted (see Non-patent Document 2). However, there has never been an example in which these human genomes and M. tuberculosis genome were simultaneously analyzed to comprehensively analyze genes involved in the onset of M. tuberculosis gene lineage from the entire genome. This is because it is rare to obtain both human genome information and M. tuberculosis genome information from a patient who has developed a disease.
  • the present invention identifies the human gene associated with tuberculosis onset specifically from the elucidation of the interaction between the human genome and the pathogen genome associated with tuberculosis onset, and in a subject infected with tuberculosis.
  • An object of the present invention is to provide a method for determining the risk of developing tuberculosis specific to each M. tuberculosis strain based on genetic information of a subject.
  • SNP Single Nucleotide Polymorphism
  • the SNP information of the human genome was obtained by DNA extracted from the blood of patients who developed tuberculosis and healthy individuals and a microarray for SNP typing.
  • the genome of infected M. tuberculosis was extracted from the patient and the genetic lineage of M. tuberculosis was identified.
  • principal component analysis was performed using SNPs information of the whole genome in order to make the genetic background of the tuberculosis patient group and the healthy subject group match.
  • tuberculosis patient group according to genetic line of infected tuberculosis bacteria and carry out association analysis to compare allele frequency of each SNPs in patient group infected with tuberculosis common strain and healthy people group
  • SNPs that show a statistical relationship in a genetic line-specific manner of M. tuberculosis have been searched, and the present invention has been completed.
  • the present invention is as follows.
  • [1] In the subject, identify the base of the single nucleotide polymorphism site of the subject's human genome that is associated with the onset of tuberculosis, and type the latent infection of the subject with the T. tuberculosis genetic line, and the subject Method for determining the risk of developing tuberculosis in a Mycobacterium tuberculosis genetic lineage-specifically by Mycobacterium tuberculosis latently infected in [2] The method of [1], wherein the M. tuberculosis genetic line to be typed is selected from the group consisting of Beijing strain, non-Beijing strain, EAI strain and non-EAI strain.
  • a primer for human genome for determining the risk of developing tuberculosis in a M. tuberculosis-infected subject which is a risk of developing tuberculosis in a Beijing strain-infected subject according to any of the following (p1) to (p14):
  • a primer for determining the risk a primer for determining the risk of developing tuberculosis in a non-Beijing strain-infected subject according to any of the following (p15) to (p26), any of the following (p27) to (p34):
  • Primers for determining the risk of developing tuberculosis in any EAI strain infected subject, or for determining the risk of developing tuberculosis in a non-EAI infected subject having any of the following (p35) to (p39)
  • Primer (p1) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs9348878) in the base sequence of S
  • a probe for determining the risk of developing tuberculosis in a T. tuberculosis-infected subject comprising A probe for determining the risk of developing tuberculosis in a Beijing strain-infected subject according to any of the following (q1) to (q14), a non-Beijing strain-infected subject according to any of the following (q15) to (q26): A probe for determining the risk of developing tuberculosis or a probe for determining the risk of developing tuberculosis in a subject infected with any of the EAI strains described in (q27) to (q34) below or (q35) A probe for determining the risk of developing tuberculosis in a non-EAI strain-infected subject of any of (q39): (q1) the 26th base in the base sequence of SEQ ID NO: 1 (base at polymorphic site of rs9348878) A probe capable of hybridizing to a region comprising (q2)
  • kits for determining the risk of developing tuberculosis comprising the primer of [5] or the probe of [6].
  • [8] In a subject, the expression level of a gene located in the vicinity of a single nucleotide polymorphism site of the subject genome which is associated with the onset of tuberculosis is measured, and a latent infection of Mycobacterium tuberculosis A method of typing strains to determine the risk of developing tuberculosis due to a latently infected M. tuberculosis in a subject.
  • tubercle bacillus in which the subject is infected is a non-Beijing strain, it is located in the vicinity of a single nucleotide polymorphism ((nb2) rs1494320) at the 26th base of the nucleotide sequence shown in SEQ ID NO: 16
  • tuberculosis species with which the subject is infected is a non-Beijing strain, it is located in the vicinity of a single nucleotide polymorphism ((nb11) rs6071980) at the 26th base of the nucleotide sequence shown in SEQ ID NO: 25
  • the present specification includes the disclosure content of Japanese Patent Application No. 2017-150296 based on which the priority of the present application is based.
  • a single nucleotide polymorphism is identified, or the expression of a gene adjacent to the single nucleotide polymorphism site is measured, whereby it is possible to use tuberculosis for each genetic line of M. tuberculosis infected with M. tuberculosis. It is possible to determine the risk of onset and efficiently sort out M. tuberculosis-infected persons who are at high risk of onset of tuberculosis from uninfected persons, treat them before onset, and prevent onset.
  • FIG. 7 shows a list of single nucleotide polymorphisms specifically associated with the onset of tuberculosis and genes in the vicinity (specifically, Beijing strain) of M. tuberculosis genetic lineage (the continuation of FIG. 1-1). It is a figure which shows the list
  • FIG. 2 shows a list of single nucleotide polymorphisms specifically associated with the onset of tuberculosis and genes in the vicinity (specifically, non-Beijing strain) of M. tuberculosis genetic lineage (continuation of FIG. 2-1). It is a figure which shows the list
  • the present invention is a method for determining the risk of developing tuberculosis (TB) in a subject based on human and M. tuberculosis genetic information.
  • determining the risk of developing tuberculosis in a subject refers to determining the likelihood or difficulty of developing tuberculosis in a subject.
  • a subject infected with, but not developing Mycobacterium tuberculosis is a subject that is latently infected with Mycobacterium tuberculosis.
  • the present invention is also a method of obtaining ancillary data to determine the risk of developing tuberculosis in a subject.
  • evaluation and determination are also referred to as prediction.
  • Tuberculosis refers to an infectious disease caused by Mycobacterium tuberculosis. The most common site is lung, but it infects organs and organs throughout the body and causes extrapulmonary tuberculosis such as pulmonary tuberculosis or tuberculosis meningitis, tuberculosis lymphadenitis.
  • the risk of developing tuberculosis can be determined, and if it is determined that the risk is high, the onset can be avoided by administering an antibiotic against M. tuberculosis in advance.
  • SNPs single nucleotide polymorphisms
  • analysis of single nucleotide polymorphism means identifying a base at a single nucleotide polymorphism site.
  • the expression of a gene located in the vicinity of a single nucleotide polymorphism site associated with the susceptibility to development of tuberculosis is measured, and the risk of developing tuberculosis is evaluated and determined based on the expression amount.
  • the gene located in the vicinity of the single nucleotide polymorphism site refers to a gene that is close in distance to the single nucleotide polymorphism site, preferably the gene that is the closest in distance.
  • the gene located in the vicinity of the single nucleotide polymorphism site is reduced in expression or enhanced in expression by the allele at the single nucleotide polymorphism site.
  • the risk of developing tuberculosis can be determined using the expression of a gene located in the vicinity of the single nucleotide polymorphism site associated with susceptibility.
  • the genetic lineage (Lineage) of the tubercle bacillus genome shows diversity, such as Beijing (Beijing) strain, EAI (East-African Indian) strain, CAS (Central Asian Strain) strain, Euro-American strain and the like.
  • Beijing strains are often infected, non-Beijing strains are collectively referred to as non-Beijing strains, and non-Beijing strains include EAI strains, CAS strains and Euro-American strains.
  • non-EAI strains include Beijing strains, CAS strains and Euro-American strains.
  • the single nucleotide polymorphisms associated with the risk of developing tuberculosis in a subject are different.
  • the risk of developing tuberculosis varies with the age of the subject, and is referred to as senile or juvenile onset depending on the age.
  • a subject who develops onset is said to be senile onset when the age of the subject is 45 years or older, and that it is juvenile onset when the age is under 45 (Mahasirimongkol S et al. J Hum Genet. 2012 Jun; 57 (6): 363-7 ).
  • Mycobacterium tuberculosis is isolated from a patient who has actually developed tuberculosis, and the genetic lineage of Mycobacterium tuberculosis is determined by typing, and single nucleotide polymorphisms across the patient's genome are analyzed.
  • patients collected from before the association analysis are compared with a group of patients having a genetic background similar to the group of healthy people. It becomes possible to extract. Also, by considering the onset age information of the patients, it is possible to extract a group of patients considered to have a common onset mechanism.
  • a group of patients extracted by such a method based on the genome information of infected tuberculosis bacteria, a group of patients infected with Beijing strain, a group of patients infected with non-Beijing strain, a group of patients infected with EAI strain, non-EAI strain infection
  • a group of patients infected with Beijing strain a group of patients infected with non-Beijing strain
  • a group of patients infected with EAI strain non-EAI strain infection
  • the present inventors have found that multiple single nucleotide polymorphisms on the human genome are associated with the onset of tuberculosis by the method of human whole genome analysis (GWAS), and completed the present invention. Is associated with the occurrence of a single nucleotide polymorphism of allyl and the risk of developing tuberculosis statistically related.
  • GWAS human whole genome analysis
  • Analysis of single nucleotide polymorphisms refers to determining the type of base at single nucleotide polymorphism site, ie, allyl, whether it is detected for one chromosome on a pair of chromosomes or for both chromosomes. Inclusion, detection for both chromosomes also includes detection of homozygosity or heterozygosity at the single nucleotide polymorphism site. Each allele that is opposite to a particular allele contained in a sample isolated from a subject can be detected and genotyped. When only one allyl is detected, it is homozygous having the allele homozygously, and when two allyls are detected, it is heterozygous having the two alleles heterozygously.
  • the risk of developing tuberculosis in a subject with latent infection with M. tuberculosis is determined by the following method.
  • Mycobacterium tuberculosis is isolated from the site of Mycobacterium tuberculosis infection in the subject. Usually, it may be isolated from the subject's sputum.
  • the sputum of M. tuberculosis patient is applied to Lowenstein-Jensen medium and cultured at 37 ° C. for 4 to 6 weeks. Genomic DNA is extracted from the cultured cells.
  • TE 10 mM Tris HCl pH 8.0, 1 mM EDTA
  • kill by heat treatment at 80 ° C. for 20 minutes add 10 mg / ml lysozyme solution, and react overnight Let it be lysed.
  • the isolated M. tuberculosis genomic DNA is typed to determine the genetic lineage. Markers and methods for typing M. tuberculosis are known, and for example, Gagneux S et al. Proc Natl Acad Sci USA A. 2006 Feb 21; 103 (8) which measures the presence or absence of a specific marker by PCR. J. Clin. Microbiol: A method of determining the Large Sequence Polymorphism (LSP) described in 2869-73. Or the DigiTag 2 method developed by the present inventors for SNP typing of the tuberculosis genome (Srilohasin P et al. J. Clin. Microbiol 2014, 52 (6): 1962-8).
  • LSP Large Sequence Polymorphism
  • the LSP determination method when the LSP determination method is classified into EAI strain, Beijing strain, CAS strain and Euro-American strain, RD239, TbD1, RD105, RD750, 7 bp deletion at pks 15 / as a genomic region to be a marker. It uses combining 5 of 1.
  • the presence or absence of the deletion of the target region can be determined by the size of the amplification product, and the genetic line can be determined.
  • EAI strain is RD239 (-) and TbD1 (+)
  • Beijing strain is RD105 (-) and TbD1 (-)
  • CAS strain is RD750 (-) and TbD1 (-)
  • Euro-American strain is TbD1 (-) and 7 bp deletion at pks 15/1.
  • the M. tuberculosis genetic line can be further classified into sublines as well as the above-mentioned classification of genetic lines. It is also possible to further subdivide and determine single nucleotide polymorphisms associated with the onset of tuberculosis for each strain.
  • the genome may be extracted from peripheral blood cells of the subject and single nucleotide polymorphisms may be analyzed, or the expression amount of a gene located in the vicinity of the single nucleotide polymorphism site may be measured.
  • the expression level for example, the expression level in blood may be measured. That is, in the present invention, M. tuberculosis which is latently infected in the subject is collected, and typing is performed to determine the genetic lineage of M. tuberculosis, and at the same time, in relation to the susceptibility to development of tuberculosis in the human genome of the subject.
  • the single nucleotide polymorphism is analyzed, or the expression level of the gene located in the vicinity of the single nucleotide polymorphism is measured.
  • the risk of developing tuberculosis is determined from single nucleotide polymorphism analysis or gene expression level of the subject for each type of finally infected M. tuberculosis.
  • the following single nucleotide polymorphisms are analyzed for a Beijing strain-infected subject, a non-Beijing strain-infected subject, an EAI strain-infected subject, and a non-EAI strain-infected subject, respectively.
  • “RsXXXXXX (X is an arbitrary number)” indicating a single nucleotide polymorphism indicates an rs number which is a reference number of a SNP database (dbSNP BUILD 137) of NCBI (National Center for Biotechnology Information).
  • the following single nucleotide polymorphism is a single nucleotide polymorphism of 1 ⁇ 10 ⁇ 5 or less when it is expressed as P value in relation to the onset of tuberculosis at the time of infection with M. tuberculosis of a specific genetic strain.
  • the P value is a value indicating whether there is a difference in the frequency of single nucleotide polymorphisms between the group of patients who developed tuberculosis and the group of healthy people who do not develop tuberculosis, and the smaller the value, the more likely the correlation is. It is judged.
  • the base at the single nucleotide polymorphism site is represented by a base in either the normal strand or reverse strand sequence registered in the SNP database. In the sequence of the other strand, they are complementary bases.
  • Non-Beijing Strain-Infected Subjects rs12144738, rs1494320, rs1712674, rs1418425, rs4688637, rs12374531, rs11784415, rs2182093, rs10798, rs4267316, rs6071980, rs743057
  • Non-EAI strain infected subject rs1820920, rs11737270, rs10832678, rs10507084, rs1440548
  • the single nucleotide polymorphism represented by the above rs number is a single nucleotide polymorphism described below.
  • odds ratio 95% confidence interval
  • P value P value
  • the odds ratio of a single nucleotide polymorphism is less than 1, a subject having minor alleles in the single nucleotide polymorphism is less likely to develop tuberculosis. For example, at 0.61, the probability of developing tuberculosis decreases 0.61 times.
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 1 is G or A.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is G
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying A allele.
  • the odds ratio is 1.98 (1.48-2.64) and the P value is 2.69 ⁇ 10 -6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 2 is A or G.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is A
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of G. That is, it can be determined that the risk of developing tuberculosis at a younger age (less than 45 years old) is higher in a subject carrying A allele (minor allele) than a subject carrying G allele.
  • the odds ratio is 2.00 (1.50-2.67) and the P value is 2.07 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 3 is C or T.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of T. That is, it can be determined that in subjects carrying C allele (minor allele) there is a higher risk of developing tuberculosis at any age than subjects carrying T allele.
  • the odds ratio is 1.63 (1.32-2.02) and the P value is 5.36 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 4 is C or T.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of T. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis in old age (45 or older) than a subject who holds T allele.
  • the odds ratio is 1.80 (1.39-2.33) and the P value is 6.97 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 5 is C or A.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele.
  • the odds ratio is 1.95 (1.46-2.60) and the P value is 5.35 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 6 is G or T.
  • the proportion of subjects who develop tuberculosis at any age is significantly smaller than in the case of T. That is, it can be determined that the risk of developing tuberculosis at any age is lower in subjects carrying G allele (minor allele) than subjects carrying T allele.
  • the odds ratio is 0.61 (0.49-0.75) and the P value is 4.31 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 7 is T or C.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying C-allyl.
  • the odds ratio is 2.08 (1.50-2.89) and the P value is 7.78 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 8 is T or C.
  • the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allyl) is at a higher risk of developing tuberculosis at any age than a subject carrying C-allyl.
  • the odds ratio is 2.49 (1.70-3.64) and the P value is 1.27 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 9 is A or G.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is A
  • the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of G. That is, it can be determined that a subject who holds A allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than a subject who holds G allele.
  • the odds ratio is 2.31 (1.60-3.35) and the P value is 5.15 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 11 is G or A.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is G
  • the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying A allele.
  • the odds ratio is 2.35 (1.63-3.38) and the P value is 2.97 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 12 is G or A.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying A allele.
  • the odds ratio is 2.36 (1.64-3.40) and the P value is 2.02 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 13 is T or G.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of G. That is, it can be determined that the subject carrying T allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying G allele.
  • the odds ratio is 2.27 (1.62-3.18) and the P value is 9.83 ⁇ 10 -7 .
  • (b14) rs 1648835 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 14 and is T or G. This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of G. That is, it can be determined that the subject carrying T allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying G allele.
  • the odds ratio is 2.33 (1.65-3.29) and the P value is 8.60 ⁇ 10 ⁇ 7 .
  • Non-Beijing Strain-Infected Subjects (nb1) rs12144738 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 15, and is C or T.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele.
  • the odds ratio is 2.22 (1.59-3.10) and the P value is 2.08 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 16 is C or T.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of T. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis in old age (45 or older) than a subject who holds T allele.
  • the odds ratio is 1.71 (1.40-1.08) and the P value is 7.84 ⁇ 10 ⁇ 8 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 17 is G or T.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is G
  • the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of T. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in the old age (45 years or older) than a subject carrying T allele.
  • the odds ratio is 1.77 (1.40-2.25) and the P value is 1.63 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 18 is T or C.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying C-allyl.
  • the odds ratio is 1.74 (1.43-2.12) and the P value is 2.54 ⁇ 10 ⁇ 8 .
  • nb5 rs4688637 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 19 and is C or A.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele.
  • the odds ratio is 2.08 (1.50-2.88) and the P value is 7.15 ⁇ 10 ⁇ 6 .
  • (nb6) rs12374531 The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 20, which is G or A.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is G
  • the proportion of subjects who develop tuberculosis in the old age of tuberculosis is significantly smaller than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a lower risk of developing tuberculosis in old age (45 years old or older) than the subject carrying A allele.
  • the odds ratio is 0.58 (0.45-0.74) and the P value is 8.54 ⁇ 10 ⁇ 6 .
  • rs11784415 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 21 and is C or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele. The odds ratio is 2.03 (1.52 to 2.74) and the P value is 2.54 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 22 is T or C.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying C-allyl.
  • the odds ratio is 2.38 (1.65 to 4.43) and the P value is 1.80 ⁇ 10 -6 .
  • (nb9) rs10798 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 23, and is A or G.
  • the base at the single nucleotide polymorphism site is A
  • the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of G. That is, it can be determined that a subject who carries A allele (minor allele) is at higher risk of developing tuberculosis at any age than a subject who carries G allele.
  • the odds ratio is 1.60 (1.32-1.95) and the P value is 2.31 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 24 is C or T.
  • the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of T. That is, it can be determined that in subjects carrying C allele (minor allele) there is a higher risk of developing tuberculosis at any age than subjects carrying T allele.
  • the odds ratio is 2.26 (1.58-32) and the P value is 5.29 ⁇ 10 ⁇ 6 .
  • (nb11) rs6071980 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 25 and is C or T.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele.
  • the odds ratio is 2.09 (1.51-2.90) and the P value is 6.77 ⁇ 10 ⁇ 6 .
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 26 is A or G.
  • the proportion of subjects who develop tuberculosis at any age is significantly smaller than in the case of G. That is, it can be determined that the risk of developing tuberculosis at any age is lower in subjects carrying A allele (minor allele) than in subjects carrying G allele.
  • the odds ratio is 0.59 (0.47-0.74) and the P value is 5.70 ⁇ 10 ⁇ 6 .
  • EAI strain infected subject (e1) rs1178938 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 27 and is C or A.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele.
  • the odds ratio is 2.37 (1.67-3.35) and the P value is 5.97 ⁇ 10 -7 .
  • the polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 28 is C or T.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele.
  • the odds ratio is 2.33 (1.65-3.30) and the P value is 9.72 ⁇ 10 ⁇ 7 .
  • (e3) rs1372667 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 29, and is G or T.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is G
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of T. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele.
  • the odds ratio is 2.29 (1.59-3.32) and the P value is 6.43 ⁇ 10 ⁇ 6 .
  • (e4) rs13174549 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 30, and is T or C.
  • T the base at the single nucleotide polymorphism site
  • the odds ratio is 0.44 (0.31-0.62) and the P value is 2.02 ⁇ 10 ⁇ 6 .
  • rs7087410 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 31, and is C or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.27 (1.58-3.25) and the P value is 5.94 ⁇ 10 ⁇ 6 .
  • rs10898382 It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 32, and is A or C. This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is A
  • the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of C. That is, it can be determined that a subject who holds A allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than a subject who holds C allele.
  • the odds ratio is 1.62 (1.32-2.00) and the P value is 3.66 ⁇ 10 ⁇ 6 .
  • Non-EAI strain infected subject rs1820920
  • the polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 35 which is C or T.
  • This single nucleotide polymorphism is highly associated with juvenile onset.
  • the base at the single nucleotide polymorphism site is C
  • the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele.
  • the odds ratio is 2.04 (1.48-2.82) and the P value is 9.18 ⁇ 10 ⁇ 6 .
  • (ne3) rs10832678 The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 37, which is G or A.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is G
  • the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying A allele.
  • the odds ratio is 1.66 (1.33-2.07) and the P value is 5.66 ⁇ 10 ⁇ 6 .
  • (ne4) rs10507084 The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 38, which is T or C.
  • This single nucleotide polymorphism is highly associated with senile onset.
  • the base at the single nucleotide polymorphism site is T, the percentage of subjects who develop tuberculosis in old age (45 years or older) is significantly smaller than in the case of C. That is, it can be determined that the subject carrying T-allyl (minor allele) has a lower risk of developing tuberculosis in old age (45 years old or older) than the subject carrying C-allyl.
  • the odds ratio is 0.58 (0.46-0.73) and the P value is 4.21 ⁇ 10 ⁇ 6 .
  • the Mycobacterium tuberculosis with which the subject is infected is a Beijing strain
  • at least one of (b1) to (b14) above preferably 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 bases
  • at least one of (nb1) to (nb12) above preferably 2 when the M. tuberculosis strain with which the subject is infected is a non-Beijing strain.
  • Tuberculosis which identifies a base of at least one, preferably 2, 3, 4, 5, 6, 7 or 8 single nucleotide polymorphic sites of the above (e1) to (e8) and which is infected with the subject
  • the strain is a non-EAI strain
  • at least one, preferably 2, 3, 4 or 5 single nucleotide polymorphism site bases of the above (ne1) to (ne5) are identified, and the types of bases To determine the risk of developing tuberculosis It is possible.
  • expression of a gene located near the single nucleotide polymorphism site in the subject may be measured.
  • expression of the gene is enhanced or diminished, it can be determined that the subject is at high risk of developing tuberculosis.
  • the method of the present invention can be applied to all human groups in the world because the single nucleotide polymorphisms described above do not exist in human groups.
  • analysis of single nucleotide polymorphism and typing of M. tuberculosis are performed simultaneously, but depending on the human population, there may be one type of M. tuberculosis infected, and in such a case, It may be omitted. For example, most Japanese are of the Beijing type.
  • Non-Beijing Strain-Infected Subjects rs12144738 FHAD1 (Forkhead Associated Phosphate binding Domain 1) (Intron) rs1494320 CD53 (Intron) rs1712674 CD53 (23 kbp 3 ') rs1418425 LRIF1 (Ligand dependent nuclear Receptor Interacting Factor 1) (21 kbp 3 ') rs4688637 PTPRG (Protein Tyrosine Phosphatase, Receptor type G) (Intron) rs12374531 PPP2R2B (Protein Phosphatase 2 Regulatory subunit Bbeta) (52 kbp 5 ') rs11784415 LRRC69 (Leucine Rich Repeat Containing 69) (Intron) rs2182093 PLCE1 (Phospholipase C Epsilon 1) (Intron) rs10798 KCNQ1 (
  • EAI strain infected subject rs1178938 C3orf 58 (Chromosome 3 open reading frame 58) (67 kbp 3 ') rs800065 C3orf 58 (Chromosome 3 open reading frame 58) (68 kbp 3 ') rs1372667 CDH12 (Cadherin 12) (31 kbp 5 ') rs13174549 EBF1 (Early B-cell Factor 1) (Intron) rs7087410 LOC220906 (106 kbp 3 ') rs10898382 DLG2 (Discs Large MAGUK scaffold protein 2) (Intron) rs951729 DLG2 (Discs Large MAGUK scaffold protein 2) (Intron) rs1658693 BTG1 (BTG anti-proliferation factor 1) (26 kbp 5 ')
  • Non-EAI strain infected subject rs 1820920 MIR 4790 (MicroRNA 4790) (301 kbp 5 ') rs11737270 FBXW7 (F-box and WD repeat domain containing 7) (254 kbp 3 ') rs10832678 C11orf 58 (Chromosome 11 open reading frame 58) (7.9 kbp 3 ') rs10507084 RMST (Rhabdoyosarcoma 2 associated transcript) (106 kbp 5 ') rs 1440548 LOC284294 (450 kbp 3 ')
  • 1-1 and 1-2 show the rs number of the single nucleotide polymorphism, the number of the human chromosome where the single nucleotide polymorphism exists, minor allele / major allele, genes located in the vicinity of the single nucleotide polymorphism, onset Shows the P value and odds ratio of each tubercle bacillus genetic line whether it is old age or young age.
  • the above single nucleotide polymorphism and the gene located in the vicinity of the single nucleotide polymorphism site can be referred to as a gene marker for determining the risk of developing tuberculosis.
  • a sample may be collected from a subject and single nucleotide polymorphisms may be analyzed for DNA and RNA of the sample. That is, genomic DNA containing single nucleotide polymorphisms may be extracted from a subject, and bases of single nucleotide polymorphism sites of alleles contained in the extracted DNA may be identified.
  • any sample can be used as long as it is a sample containing chromosomal DNA, and examples thereof include blood, skin, oral mucosa, hair, urine, nails, cells and the like. From these samples, nucleic acids such as chromosomes, DNA or RNA may be isolated and analyzed according to a conventional method.
  • the analysis of single nucleotide polymorphism can be performed by a conventional gene polymorphism analysis method.
  • a conventional gene polymorphism analysis method for example, an analysis method by sequence analysis in which the sequence is directly determined by a known method such as the dideoxy method or Maxam-Gilbert method, a probe specific for gene polymorphism or a hybridization using a microarray (DNA chip) on which the probe is immobilized Methods, various methods using primers specific for gene polymorphism, etc., and more specifically, primer extension method (TaqMan (registered trademark) method), PCR-SSCP method, single-strand conformation polymorphism analysis (SSCP; single strand conformation polymorphism), Invader method, single nucleotide primer method, PCR method, NASBA method, LCR method, SDA method, LAMP method, method using restriction fragment length polymorphism (RFLP), denaturing gradient gel electrophoresis Method (DGGE), Method using chemical cleavage of mismatch site
  • DigiTag 2 method may be used in which each single nucleotide polymorphism genotype is converted to an oligo DNA tag and analysis is performed by hybridization with a DNA chip.
  • the DigiTag 2 method is described in Srilohasin P et al. J. Clin. Microbiol. 2014, 52 (6): 1962-8, Nishida N et al., Analytical Biochemistry 346 (2): 281-288, Nishida et al., Analytical Biochemistry. 364 (1): 78-85 and the like.
  • the analysis by sequence analysis can be performed by a conventional method. Specifically, a sequence reaction is performed using a primer set at the position of several tens of bases on the 5 'side of the single nucleotide polymorphism site, and the base of the single nucleotide polymorphism site can be determined from the analysis result it can.
  • the method of using a primer is carried out by amplifying a nucleic acid sample isolated from a subject using a primer corresponding to a part of a gene sequence containing a single nucleotide polymorphism site. That is, for example, a nucleic acid sample isolated from a subject when each primer is used, using a primer completely or almost completely complementary to one allele and a primer completely or almost completely complementary to the other allele.
  • the allele of single nucleotide polymorphism can be identified depending on whether or not is amplified. Alternatively, only a primer corresponding to one of the alleles may be used.
  • the method using a probe consists of an oligonucleotide corresponding to a part of the gene sequence containing a single nucleotide polymorphism site or a complementary sequence thereof, or an oligonucleotide consisting of a sequence capable of hybridizing to these sequences under stringent conditions.
  • the probe can be used for analysis by hybridization of a nucleic acid sample isolated from a subject, or a nucleic acid sample amplified by a known method such as PCR. That is, complete or almost complete (for example, 70% or more sequence identity, preferably 80% or more sequence identity, of the base sequence portion continuous to the target single nucleotide polymorphism site) to one allyl.
  • Each probe using a probe complementary to% or more of sequence identity, particularly preferably having a sequence identity of 95% or more, and a probe completely or almost completely complementary only to the other allele can be identified depending on whether it hybridizes with the nucleic acid sample isolated from the subject or the nucleic acid sample amplified from the subject when it has been. Alternatively, only probes corresponding to one of the alleles may be used.
  • the hybridization conditions may be any conditions sufficient to distinguish single nucleotide polymorphisms, for example, hybridization occurs when the single nucleotide polymorphism site is a specific allele, while hybridization occurs when the other alleles
  • Conditions that do not cause soybeans, such as stringent conditions can be set as appropriate by those skilled in the art.
  • the probe may be used as a DNA chip (microarray) by fixing one end to a substrate. In this case, even if only a probe corresponding to one gene polymorphism site is immobilized, a probe corresponding to a plurality of single nucleotide polymorphism sites may be immobilized on the DNA chip.
  • Probes and primers for detecting single nucleotide polymorphisms can be appropriately designed based on the sequence information of single nucleotide polymorphisms.
  • the probe consists of a nucleotide sequence (preferably, a DNA fragment) consisting of a nucleotide sequence containing a single nucleotide polymorphism site or a nucleotide sequence complementary to the nucleotide sequence or a sequence capable of hybridizing to the sequences under stringent conditions.
  • the number of bases is 5 to 50, preferably 10 to 30, and more preferably 10 to 25.
  • the primer is a primer capable of identifying an allele at a single nucleotide polymorphism site, and is, for example, a sequence capable of amplifying a region having a sequence containing a single nucleotide polymorphism site.
  • These primers may contain a sequence containing a single nucleotide polymorphism site, and may be 3 'and 5' to a region containing a single nucleotide polymorphism site (preferably a region of 40 to 1000 bases in length).
  • the primer is composed of a nucleotide sequence (preferably a DNA fragment) consisting of a nucleotide sequence containing a single nucleotide polymorphism site or a nucleotide sequence complementary to the nucleotide sequence or a sequence capable of hybridizing to these sequences under stringent conditions.
  • a nucleotide sequence preferably a DNA fragment
  • the number of bases is 5 to 50, preferably 10 to 30, and more preferably 15 to 25.
  • the probe or primer may contain several, preferably 1 to 5, more preferably 1 or 2, particularly preferably 1 mismatch in the continuous base sequence including the single nucleotide polymorphism site. Good.
  • the present invention relates to a probe used to analyze the above single nucleotide polymorphism and a primer used to amplify a DNA fragment containing a single nucleotide polymorphism site to analyze the single nucleotide polymorphism (preferably, at least a pair of primer sets) ). It also includes a DNA chip on which a probe is immobilized. Furthermore, a kit for analyzing the above-mentioned single nucleotide polymorphism site containing a probe, a DNA chip, and a primer is also included.
  • the kit may additionally contain a restriction enzyme, a polymerase, nucleoside triphosphate, a nucleic acid labeling molecule, a buffer, an instruction manual for the kit, etc. which are used for analysis of single nucleotide polymorphisms.
  • the following can be mentioned as a probe or a primer used for analysis of a single nucleotide polymorphism site.
  • a primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs9348878) in the base sequence of SEQ ID NO: 1 (p2) A primer capable of amplifying a region containing the 26th base (a base at the polymorphic site of rs2070600) in the nucleotide sequence of SEQ ID NO: 2 (p3) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs401864) in the nucleotide sequence of SEQ ID NO: 3 (p4)
  • a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs673119) in the nucleotide sequence of SEQ ID NO: 4 (p5) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1321267) in the nucleotide sequence of SEQ ID NO:
  • a primer capable of amplifying a region including the 26th base (base of polymorphic site of rs12144738) in the nucleotide sequence of SEQ ID NO: 15 (p16) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16 (p17) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1712674) in the nucleotide sequence of SEQ ID NO: 17 (p18)
  • a primer capable of amplifying a region containing the 26th base (a base at the polymorphic site of rs1418425) in the nucleotide sequence of SEQ ID NO: 18 (p19) A primer capable of amplifying a region containing the 26th base (a base of polymorph
  • a primer capable of amplifying a region including the 26th base (base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27 (p28) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs8000065) in the nucleotide sequence of SEQ ID NO: 28 (p29) A primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1372667) in the nucleotide sequence of SEQ ID NO: 29 (p30)
  • a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs13174549) in the nucleotide sequence of SEQ ID NO: 30 (p31) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs)
  • a primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs1820920) in the nucleotide sequence of SEQ ID NO: 35 A primer capable of amplifying a region including the 26th base (base of polymorphic site of rs11737270) in the nucleotide sequence of SEQ ID NO: 36 (p37) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10832678) in the base sequence of SEQ ID NO: 37 (p38)
  • a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10507084) in the nucleotide sequence of SEQ ID NO: 38 A primer capable of amplifying a region containing the 26th base (a base at polymorphic site of rs 144
  • Probes to determine the risk of developing tuberculosis in a Beijing strain-infected subject (q1) A probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs9348878) in the base sequence of SEQ ID NO: 1 (q2) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs2070600) in the base sequence of SEQ ID NO: 2 (q3) A probe capable of hybridizing to a region containing the 26th base (base of polymorphic site of rs401864) in the base sequence of SEQ ID NO: 3 (q4) A probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs673119) in the base sequence of SEQ ID NO: 4 (q5) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs1321267) in the base sequence of SEQ ID NO: 5 (q6) A probe
  • Probes for determining the risk of developing tuberculosis in non-Beijing strains infected subjects (q15) A probe capable of hybridizing to a region including the 26th base (a base at the polymorphic site of rs12144738) in the nucleotide sequence of SEQ ID NO: 15 (q16) a probe capable of hybridizing to a region containing the 26th base (the base at the polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16 (q17) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs1712674) in the base sequence of SEQ ID NO: 17 (q18) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1418425) in the base sequence of SEQ ID NO: 18 (q19) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of r
  • Probe for determining the risk of developing tuberculosis in an EAI strain infected subject a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27 (q28) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs8000065) in the base sequence of SEQ ID NO: 28 (q29) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1372667) in the base sequence of SEQ ID NO: 29 (q30) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs13174549) in the base sequence of SEQ ID NO: 30 (q31) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs7087410)
  • Probes for determining the risk of developing tuberculosis in non-EAI strain infected subjects (q35) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs1820920) in the nucleotide sequence of SEQ ID NO: 35 (q36) a probe capable of hybridizing to a region containing the 26th base (the base at the polymorphic site of rs11737270) in the nucleotide sequence of SEQ ID NO: 36 (q37) a probe capable of hybridizing to a region containing the 26th base (the base at the polymorphic site of rs10832678) in the nucleotide sequence of SEQ ID NO: 37 (q38) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10507084) in the base sequence of SEQ ID NO: 38 (q39) a probe capable of hybridizing to a region containing the 26th base (the base of
  • the Mycobacterium tuberculosis with which the subject is infected is a Beijing strain
  • at least one of (p1) to (p14) above preferably 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 primers
  • at least one of (p15) to (p26) above preferably 2, when the M.
  • tuberculosis strain with which the subject is infected is a non-Beijing strain
  • 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 primers are used and the tubercle bacillus infecting the subject is the EAI strain
  • the above (p27) to (p34) Using at least one, preferably 2, 3, 4, 5, 6, 7 or 8 primers of the above (p35) when the tubercle bacillus infecting the subject is a non-EAI strain.
  • the single nucleotide polymorphism may be identified using at least one, preferably 2, 3, 4 or 5 primers of to (p39).
  • the primer is preferably used as a primer pair of forward and reverse primers.
  • the M. tuberculosis organism with which the subject is infected is a Beijing strain
  • at least one of the above (q1) to (q14), preferably 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, or 14 probes, and at least one of (q15) to (q26) described above is used, preferably when the M. tuberculosis strain with which the subject is infected is a non-Beijing strain.
  • 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 probes are used and the tubercle bacillus infecting the subject is the EAI strain
  • the above (q27) Using at least one, preferably 2, 3, 4, 5, 6, 7 or 8 probes of (q34), when the M. tuberculosis strain with which the subject is infected is a non-EAI strain,
  • a single nucleotide polymorphism may be identified using at least one, preferably 2, 3, 4 or 5 probes of q35) to (q39).
  • the present invention includes a reagent or kit for determining the risk of developing tuberculosis, which comprises the above-described primer or probe.
  • the expression of the gene located in the vicinity of the single nucleotide polymorphism site may be determined by measuring the mRNA of each gene or measuring the expressed protein.
  • mRNA is measured.
  • the mRNA or protein may be measured from tissue or cells.
  • RNA may be extracted from the tissue or cell, reverse transcribed to cDNA, and the cDNA may be measured.
  • the measurement of cDNA can be performed using a probe or a primer that hybridizes complementarily to each gene using sequence information of each gene.
  • the measurement using a probe or a primer can be performed according to the method of detecting the single nucleotide polymorphism described above.
  • the measurement of the protein can be performed by extracting the protein from tissues or cells, and using an antibody such as a monoclonal antibody against the protein by an immunoassay using an antigen-antibody reaction. In addition, it can also be measured by immunohistochemistry, immunocytochemistry staining using the above-described antibody, on collected tissues or cells.
  • the subject is given (1) rifampicin, (2) isoniazid, (3) streptomycin, (4) ethambutol, (5) pyrazinamide, etc.
  • Antibiotics may be combined as appropriate and administered over several months. For example, (1) and (2) and (4) or (3) and (5) may be administered for about 2 months, and thereafter (1) and (2) may be administered for about 4 months.
  • the present invention is based on the analysis results for tuberculosis and healthy people collected in Thailand.
  • the diagnosis of tuberculosis was based on the culture determination of M. tuberculosis from the sputum of the patient, and those that were positive were determined to be those who developed tuberculosis. Patients who were coinfected with the HIV virus are excluded. Healthy persons are those who have no history of tuberculosis. DNA was extracted from the patient's blood and infected M. tuberculosis.
  • the SNP information of the human genome was obtained by Illumina Human610-Quad v1.0 or Illumina Human OmniExpressExome-8 v1.2, which are microarrays for SNP typing manufactured by Illumina. Genotype information derived from 338, 476 SNPs common to the two arrays is to be analyzed in the process of the present invention. For quality control of sample data, a sample with a genotype determination rate of 98% or more for SNPs in the entire genome was adopted.
  • the genetic strain of M. tuberculosis was identified using the extracted M. tuberculosis genome.
  • the determination was carried out using a large sequence polymorphism (LSP) method based on PCR using the extracted genomic DNA as a template.
  • LSP large sequence polymorphism
  • EAI strain is RD239 (-) and TbD1 (+)
  • Beijing strain is RD105 (-) and TbD1 (-)
  • CAS strain is RD750 (-) and TbD1 (-)
  • Euro-American strain is TbD1 (-) and 7 bp deletion at pks 15/1.
  • the other strains were TbD1 (-) and all other four regions (+).
  • Classification was also performed by spoligotyping, but it was consistent with the classification result by the LSP method.
  • non-Beijing strains are collectively referred to as non-Beijing strains, and non-Beijing strains are classified as EAI strains, CAS strains and Euro-American strains. Is included.
  • EAI strain is frequently infected
  • strains other than the EAI strain are collectively referred to as non-EAI strains, and non-EAI strains include Beijing strains, CAS strains and Euro-American strains.
  • a combination of classification of patient groups using patient onset age information is combined to analyze a group of patients considered to have a common onset mechanism, and is unique at the genetic lineage of M. tuberculosis and at a specific onset age
  • the patients were classified according to their age of onset according to the previous report (Mahasirimongkol S et al. J Hum Genet. 2012 Jun; 57 (6): 363-7) according to age group older than 45 and younger group younger than 45 years.
  • the genetic strains of M. tuberculosis found by this search specifically include SNPs associated with the onset of tuberculosis and genes in the vicinity thereof (FIG. 1 to 4).
  • chi-square test is performed on counts of alleles between a group of tuberculosis patients and a group of healthy subjects to calculate P values.
  • the genomic inflation factor which is an indicator of genetic background gap between TB patients and healthy people, was within the acceptable range of 1.066.
  • P values lower than 1E-05 are judged to be suggested associated (suggestively associated).
  • the raw data of genotyping was confirmed for all SNPs whose P value was less than 1E-05, and it was confirmed that there was no problem in genotyping.
  • the number of specimens in the group of patients infected with the strain of Beijing stock in the collected population is smaller than that in the group of all patients who do not consider M. tuberculosis genetic line information (the column of Total in the table).
  • Fourteen SNPs were identified for which more statistically significant associations (P values) were found. These SNPs did not find significant association in the non-Beijing strain-infected patient group. Ten genes were found as the nearest genes to these 14 SNPs (in the table, Gene items).
  • the gene expression level is significantly increased in the patient (before the start of treatment) (PTB_00) compared to the healthy person (Control), 2 months after treatment (PTB_02), 12 months (PTB_02) At PTB_12), the expression level was reduced.
  • the gene expression level of the CD53 gene and the MAFB gene is higher in patients with tuberculosis (Pulmonary TB, PTB) than in patients with latent infection (Latent TB, LTB) infected with but not developing tuberculosis. It was FIG.
  • FIG. 5 shows the results of the CD53 gene
  • FIG. 6 shows the results of the MAFB gene.
  • A indicates the expression level at healthy control (Control), patient (before treatment start, PTB_00), 2 months after treatment (PTB_02) and 12 months (PTB_12), and B indicates healthy people (Control)
  • the expression levels in M. tuberculosis-infected patients (latent infection) (LTB) and (tuberculous onset patients) (PTB) are shown.
  • LTB tumor infection
  • PTB tumor tuberculous onset patients
  • the risk of developing tuberculosis can be determined for each genetic strain of Mycobacterium tuberculosis, and used for diagnosing the possibility of developing tuberculosis Can. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

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Abstract

Provided is a method for evaluating an onset risk of tuberculosis on the basis of genetic information of a subject, said subject being infected with Mycobacterium tuberculosis, specifically to each genetic lineage of M. tuberculosis. The method comprises: identifying a base at a single nucleotide polymorphic site in the subject's genome relating to the onset of tuberculosis in the subject; typing the genetic lineage of M. tuberculosis latently infecting the subject; and then determining the risk of the onset of tuberculosis caused by the latently infecting M. tuberculosis in the subject specifically to the genetic lineage of M. tuberculosis.

Description

結核菌遺伝系統特異的に結核症発症のリスクを判定する方法Method of determining the risk of developing tuberculosis specific to Mycobacterium tuberculosis genetic lineage
　本発明は、結核症の発症するリスクを判定する方法に関する。 The present invention relates to a method of determining the risk of developing tuberculosis.
　結核症発症と関連するヒト遺伝子多型の同定は候補遺伝子研究等によりゲノム全域を対象として様々に行われてきた(非特許文献１を参照）。一方、結核菌ゲノムについても発症と関連する遺伝子変異の研究が行われている（非特許文献２を参照）。しかしながら、これらのヒトゲノムと結核菌ゲノムを同時に解析し、結核菌遺伝系統特異的に発症に関わる遺伝子をゲノム全域から網羅的に解析した例はこれまでになかった。これは、疾患を発症した患者からヒトゲノム情報と結核菌ゲノム情報をともに取得することは稀であるためである。 Identification of human gene polymorphisms associated with the onset of tuberculosis has been variously performed on the entire genome by candidate gene research and the like (see Non-Patent Document 1). On the other hand, researches on gene mutations associated with the onset of M. tuberculosis genome have also been conducted (see Non-patent Document 2). However, there has never been an example in which these human genomes and M. tuberculosis genome were simultaneously analyzed to comprehensively analyze genes involved in the onset of M. tuberculosis gene lineage from the entire genome. This is because it is rare to obtain both human genome information and M. tuberculosis genome information from a patient who has developed a disease.
　本発明は、結核症発症に関連するヒトゲノム及び病原菌ゲノムの相互作用の解明から、結核菌遺伝系統特異的に結核症発症に関連するヒト遺伝子を同定し、結核菌に感染している被験体において、被験体の遺伝子情報に基づいて、結核菌系統ごとに特異的に、結核症発症のリスクを判定する方法の提供を目的とする。 The present invention identifies the human gene associated with tuberculosis onset specifically from the elucidation of the interaction between the human genome and the pathogen genome associated with tuberculosis onset, and in a subject infected with tuberculosis. An object of the present invention is to provide a method for determining the risk of developing tuberculosis specific to each M. tuberculosis strain based on genetic information of a subject.
　本発明者らは、ヒトゲノム全域の一塩基多型(SNP:Single Nucleotide Polymorphism)の情報を取得することに加え、結核菌のゲノム情報も取得し、２つの情報を併せて結核症発症との関連解析を行った。この解析により、ヒトゲノムと結核菌ゲノムを独立に解析していた際には関連が同定できない結核菌遺伝系統特異的に結核症発症と関連したヒトゲノム中のSNPs及びその近傍の遺伝子を同定した。 In addition to acquiring information on single nucleotide polymorphism (SNP: Single Nucleotide Polymorphism) throughout the human genome, the inventors acquired genomic information on M. tuberculosis and combined the two pieces of information together with the development of tuberculosis. The analysis was done. This analysis identified SNPs in the human genome and genes in the vicinity of the human genome specifically associated with M. tuberculosis genetic lineage that can not be identified when the human genome and M. tuberculosis genome were analyzed independently.
　ヒトゲノムのSNP情報は、結核症を発症した患者及び健常者の血液より抽出したDNA及びSNPタイピング用マイクロアレイによって得た。 The SNP information of the human genome was obtained by DNA extracted from the blood of patients who developed tuberculosis and healthy individuals and a microarray for SNP typing.
　同時に、患者より感染結核菌のゲノムを抽出し、結核菌の遺伝系統の判別を行った。解析においては、結核症患者群と健常者群の持つ遺伝的背景をそろえる為にゲノム全域のSNPs情報を用いて主成分分析を行った。また、患者の発症年齢情報を用いての患者群の分類も行った。 At the same time, the genome of infected M. tuberculosis was extracted from the patient and the genetic lineage of M. tuberculosis was identified. In the analysis, principal component analysis was performed using SNPs information of the whole genome in order to make the genetic background of the tuberculosis patient group and the healthy subject group match. We also classified patient groups using patient age information.
　そして、感染している結核菌の遺伝系統ごとに結核症患者群を分類し、共通の遺伝系統の結核菌に感染した患者群と健常者群における各SNPｓのアリル頻度を比較する関連解析を実施することにより、結核菌の遺伝系統特異的に統計的な関連を示すSNPｓを探索し、本発明を完成させるに至った。 And we classify tuberculosis patient group according to genetic line of infected tuberculosis bacteria and carry out association analysis to compare allele frequency of each SNPs in patient group infected with tuberculosis common strain and healthy people group By doing this, SNPs that show a statistical relationship in a genetic line-specific manner of M. tuberculosis have been searched, and the present invention has been completed.
　すなわち、本発明は以下のとおりである。
[１]　被験体において、結核症の発症と関連している被験体ヒトゲノムの一塩基多型部位の塩基を同定し、かつ被験体に潜伏感染している結核菌遺伝系統をタイピングし、被験体において潜伏感染している結核菌により結核菌遺伝系統特異的に、結核症を発症するリスクを判定する方法。
[２]　タイピングされる結核菌遺伝系統が、北京株、非北京株、EAI株及び非EAI株からなる群から選択される、[１]の方法。
[３]　被験体が感染している結核菌が北京株であるときに、以下の(b1)～(b14)の少なくとも１つの一塩基多型部位の塩基を同定し、被験体が感染している結核菌が非北京株であるときに、以下の(nb1)～(nb12)の少なくとも１つの一塩基多型部位の塩基を同定し、被験体が感染している結核菌がEAI株であるときに、以下の(e1)～(e8)の少なくとも１つの一塩基多型部位の塩基を同定し、被験体が感染している結核菌が非EAI株であるときに、以下の(ne1)～(ne5)の少なくとも１つの一塩基多型部位の塩基を同定することを含む、[１]又は[２]の方法：
(b1)　rs9348878
　配列番号１で示される塩基配列の26番目の塩基における多型であり、G又はAである；
(b2)　rs2070600
　配列番号２で示される塩基配列の26番目の塩基における多型であり、A又はGである；
(b3)　rs401864
　配列番号３で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(b4)　rs673119
　配列番号４で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(b5)　rs1321267
　配列番号５で示される塩基配列の26番目の塩基における多型であり、C又はAである；
(b6)　rs2076625
　配列番号６で示される塩基配列の26番目の塩基における多型であり、G又はTである；
(b7)　rs7142055
　配列番号７で示される塩基配列の26番目の塩基における多型であり、T又はCである；
(b8)　rs1157619
　配列番号８で示される塩基配列の26番目の塩基における多型であり、T又はCである；
(b9)　rs4924568
　配列番号９で示される塩基配列の26番目の塩基における多型であり、A又はGである；
(b10)　rs1899820
　配列番号10で示される塩基配列の26番目の塩基における多型であり、A又はCである；
(b11)　rs2695163
　配列番号11で示される塩基配列の26番目の塩基における多型であり、G又はAである；
(b12)　rs1197772
　配列番号12で示される塩基配列の26番目の塩基における多型であり、G又はAである；
(b13)　rs1081022
　配列番号13で示される塩基配列の26番目の塩基における多型であり、T又はGである；
(b14)　rs1648835
　配列番号14で示される塩基配列の26番目の塩基における多型であり、T又はGである；
(nb1)　rs12144738
　配列番号15で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(nb2)　rs1494320
　配列番号16で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(nb3)　rs1712674
　配列番号17で示される塩基配列の26番目の塩基における多型であり、G又はTである；
(nb4)　rs1418425
　配列番号18で示される塩基配列の26番目の塩基における多型であり、T又はCである；
(nb5)　rs4688637
　配列番号19で示される塩基配列の26番目の塩基における多型であり、C又はAである；
(nb6)　rs12374531
　配列番号20で示される塩基配列の26番目の塩基における多型であり、G又はAである；
(nb7)　rs11784415
　配列番号21で示される塩基配列の26番目の塩基における多型であり、C又はAである；
(nb8)　rs2182093
　配列番号22で示される塩基配列の26番目の塩基における多型であり、T又はCである；
(nb9)　rs10798
　配列番号23で示される塩基配列の26番目の塩基における多型であり、A又はGである；
(nb10)　rs4267316
　配列番号24で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(nb11)　rs6071980
　配列番号25で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(nb12)　rs743057
　配列番号26で示される塩基配列の26番目の塩基における多型であり、A又はGである；
(e1)　rs1178938
　配列番号27で示される塩基配列の26番目の塩基における多型であり、C又はAである；
(e2)　rs800065
　配列番号28で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(e3)　rs1372667
　配列番号29で示される塩基配列の26番目の塩基における多型であり、G又はTである；
(e4)　rs13174549
　配列番号30で示される塩基配列の26番目の塩基における多型であり、T又はCである；
(e5)　rs7087410
　配列番号31で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(e6)　rs10898382
　配列番号32で示される塩基配列の26番目の塩基における多型であり、A又はCである；
(e7)　rs951729
　配列番号33で示される塩基配列の26番目の塩基における多型であり、A又はCである；
(e8)　rs1658693
　配列番号34で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(ne1)　rs1820920
　配列番号35で示される塩基配列の26番目の塩基における多型であり、C又はTである；
(ne2)　rs11737270
　配列番号36で示される塩基配列の26番目の塩基における多型であり、G又はAである； (ne3)　rs10832678
　配列番号37で示される塩基配列の26番目の塩基における多型であり、G又はAである；
(ne4)　rs10507084
　配列番号38で示される塩基配列の26番目の塩基における多型であり、T又はCである；又は
(ne5)　rs1440548
　配列番号39で示される塩基配列の26番目の塩基における多型であり、C又はTである。
[４]（１）　配列番号１で示される塩基配列の26番目の一塩基多型部位（(b1)　rs9348878）の塩基がGの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（２）　配列番号２で示される塩基配列の26番目の一塩基多型部位（(b2)　rs2070600）の塩基がAの場合に、Gの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（３）　配列番号３で示される塩基配列の26番目の一塩基多型部位（(b3)　rs401864）の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
（４）　配列番号４で示される塩基配列の26番目の一塩基多型部位（(b4)　rs673119）の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（５）　配列番号５で示される塩基配列の26番目の一塩基多型部位（(b5)　rs1321267）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（６）　配列番号６で示される塩基配列の26番目の一塩基多型部位（(b6)　rs2076625）の塩基がGの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが低いと判定し、
（７）　配列番号７で示される塩基配列の26番目の一塩基多型部位（(b7)　rs7142055）の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（８）　配列番号８で示される塩基配列の26番目の一塩基多型部位（(b8)　rs1157619）の塩基がTの場合に、Cの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
（９）　配列番号９で示される塩基配列の26番目の一塩基多型部位（(b9)　rs4924568）の塩基がAの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（10）　配列番号10で示される塩基配列の26番目の一塩基多型部位（(b10)　rs1899820）の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（11）　配列番号11で示される塩基配列の26番目の一塩基多型部位（(b11)　rs2695163）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（12）　配列番号12で示される塩基配列の26番目の一塩基多型部位（(b12)　rs1197772）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（13）　配列番号13で示される塩基配列の26番目の一塩基多型部位（(b13)　rs1081022）の塩基がTの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（14）　配列番号14で示される塩基配列の26番目の一塩基多型部位（(b14)　rs1648835）の塩基がTの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（15）　配列番号15で示される塩基配列の26番目の一塩基多型部位（(nb1)　rs12144738）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（16）　配列番号16で示される塩基配列の26番目の一塩基多型部位（(nb2)　rs1494320）の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（17）　配列番号17で示される塩基配列の26番目の一塩基多型部位（(nb3)　rs1712674）の塩基がGの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（18）　配列番号18で示される塩基配列の26番目の一塩基多型部位（(nb4)　rs1418425）の塩基がTの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（19）　配列番号19で示される塩基配列の26番目の一塩基多型部位（(nb5)　rs4688637）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（20）　配列番号20で示される塩基配列の26番目の一塩基多型部位（(nb6)　rs12374531）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが低いと判定し、
（21）　配列番号21で示される塩基配列の26番目の一塩基多型部位（(nb7)　rs11784415）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（22）　配列番号22で示される塩基配列の26番目の一塩基多型部位（(nb8)　rs2182093）の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（23）　配列番号23で示される塩基配列の26番目の一塩基多型部位（(nb9)　rs10798）の塩基がAの場合に、Gの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
（24）　配列番号24で示される塩基配列の26番目の一塩基多型部位（(nb10)　rs4267316）の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
（25）　配列番号25で示される塩基配列の26番目の一塩基多型部位（(nb11)　rs6071980）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（26）　配列番号26で示される塩基配列の26番目の一塩基多型部位（(nb12)　rs743057）の塩基がAの場合に、Gの場合に比べあらゆる年齢において結核症を発症するリスクが低いと判定し、
（27）　配列番号27で示される塩基配列の26番目の一塩基多型部位（(e1)　rs1178938）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（28）　配列番号28で示される塩基配列の26番目の一塩基多型部位（(e2)　rs800065）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（29）　配列番号29で示される塩基配列の26番目の一塩基多型部位（(e3)　rs1372667）の塩基がGの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（30）　配列番号30で示される塩基配列の26番目の一塩基多型部位（(e4)　rs13174549）の塩基がTの場合に、Cの場合に比べあらゆる年齢において結核症を発症するリスクが低いと判定し、
（31）　配列番号31で示される塩基配列の26番目の一塩基多型部位（(e5)　rs7087410）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（32）　配列番号32で示される塩基配列の26番目の一塩基多型部位（(e6)　rs10898382）の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（33）　配列番号33で示される塩基配列の26番目の一塩基多型部位（(e7)　rs951729）の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（34）　配列番号34で示される塩基配列の26番目の一塩基多型部位（(e8)　rs1658693）の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが低いと判定し、
（35）　配列番号35で示される塩基配列の26番目の一塩基多型部位（(ne1)　rs1820920）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（36）　配列番号36で示される塩基配列の26番目の一塩基多型部位（(ne2)　rs11737270）の塩基がGの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
（37）　配列番号37で示される塩基配列の26番目の一塩基多型部位（(ne3)　rs10832678）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
（38）　配列番号38で示される塩基配列の26番目の一塩基多型部位（(ne4)　rs10507084）の塩基がTの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが低いと判定し、又は
（39）　配列番号39で示される塩基配列の26番目の一塩基多型部位（(ne5)　rs1440548）の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定する、
[３]の方法。
[５]　結核菌感染被験体における結核症発症のリスクを判定するためのヒトゲノムに対するプライマーであって、以下の(p1)～(p14)のいずれかの北京株感染被験体における結核症発症のリスクを判定するためのプライマー、以下の(p15)～(p26)のいずれかの非北京株感染被験体における結核症発症のリスクを判定するためのプライマー、以下の(p27)～(p34)のいずれかのEAI株感染被験体における結核症発症のリスクを判定するためのプライマー、又は以下の(p35)～(p39)のいずれかの非EAI株感染被験体における結核症発症のリスクを判定するためのプライマー：
(p1)　配列番号１の塩基配列における26番目の塩基（rs9348878の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p2)　配列番号２の塩基配列における26番目の塩基（rs2070600の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p3)　配列番号３の塩基配列における26番目の塩基（rs401864の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p4)　配列番号４の塩基配列における26番目の塩基（rs673119の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p5)　配列番号５の塩基配列における26番目の塩基（rs1321267の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p6)　配列番号６の塩基配列における26番目の塩基（rs2076625の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p7)　配列番号７の塩基配列における26番目の塩基（rs7142055の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p8)　配列番号８の塩基配列における26番目の塩基（rs1157619の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p9)　配列番号９の塩基配列における26番目の塩基（rs4924568の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p10)　配列番号10の塩基配列における26番目の塩基（rs1899820の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p11)　配列番号11の塩基配列における26番目の塩基（rs2695163の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p12)　配列番号12の塩基配列における26番目の塩基（rs1197772の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p13)　配列番号13の塩基配列における26番目の塩基（rs1081022の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p14)　配列番号14の塩基配列における26番目の塩基（rs1648835の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p15)　配列番号15の塩基配列における26番目の塩基（rs12144738の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p16)　配列番号16の塩基配列における26番目の塩基（rs1494320の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p17)　配列番号17の塩基配列における26番目の塩基（rs1712674の多型部位の塩基）を含む領域を増幅することができるプライマー
(p18)　配列番号18の塩基配列における26番目の塩基（rs1418425の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p19)　配列番号19の塩基配列における26番目の塩基（rs4688637の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p20)　配列番号20の塩基配列における26番目の塩基（rs12374531の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p21)　配列番号21の塩基配列における26番目の塩基（rs11784415の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p22)　配列番号22の塩基配列における26番目の塩基（rs2182093の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p23)　配列番号23の塩基配列における26番目の塩基（rs10798の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p24)　配列番号24の塩基配列における26番目の塩基（rs4267316の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p25)　配列番号25の塩基配列における26番目の塩基（rs6071980の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p26)　配列番号26の塩基配列における26番目の塩基（rs743057の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p27)　配列番号27の塩基配列における26番目の塩基（rs1178938の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p28)　配列番号28の塩基配列における26番目の塩基（rs800065の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p29)　配列番号29の塩基配列における26番目の塩基（rs1372667の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p30)　配列番号30の塩基配列における26番目の塩基（rs13174549の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p31)　配列番号31の塩基配列における26番目の塩基（rs7087410の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p32)　配列番号32の塩基配列における26番目の塩基（rs10898382の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p33)　配列番号33の塩基配列における26番目の塩基（rs951729の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p34)　配列番号34の塩基配列における26番目の塩基（rs1658693の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p35)　配列番号35の塩基配列における26番目の塩基（rs1820920の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p36)　配列番号36の塩基配列における26番目の塩基（rs11737270の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p37)　配列番号37の塩基配列における26番目の塩基（rs10832678の多型部位の塩基）を含む領域を増幅することができるプライマー；
(p38)　配列番号38の塩基配列における26番目の塩基（rs10507084の多型部位の塩基）を含む領域を増幅することができるプライマー；又は
(p39)　配列番号39の塩基配列における26番目の塩基（rs1440548の多型部位の塩基）を含む領域を増幅することができるプライマー。
[６]　結核菌感染被験体における結核症発症のリスクを判定するためのプローブであって、
以下の(q1)～(q14)のいずれかの北京株感染被験体における結核症発症のリスクを判定するためのプローブ、以下の(q15)～(q26)のいずれかの非北京株感染被験体における結核症発症のリスクを判定するためのプローブ、以下の(q27)～(q34)のいずれかのEAI株感染被験体における結核症発症のリスクを判定するためのプローブ、又は以下の(q35)～(q39)のいずれかの非EAI株感染被験体における結核症発症のリスクを判定するためのプローブ：(q1)　配列番号１の塩基配列における26番目の塩基（rs9348878の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q2)　配列番号２の塩基配列における26番目の塩基（rs2070600の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q3)　配列番号３の塩基配列における26番目の塩基（rs401864の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q4)　配列番号４の塩基配列における26番目の塩基（rs673119の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q5)　配列番号５の塩基配列における26番目の塩基（rs1321267の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q6)　配列番号６の塩基配列における26番目の塩基（rs2076625の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q7)　配列番号７の塩基配列における26番目の塩基（rs7142055の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q8)　配列番号８の塩基配列における26番目の塩基（rs1157619の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q9)　配列番号９の塩基配列における26番目の塩基（rs4924568の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q10)　配列番号10の塩基配列における26番目の塩基（rs1899820の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q11)　配列番号11の塩基配列における26番目の塩基（rs2695163の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q12)　配列番号12の塩基配列における26番目の塩基（rs1197772の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q13)　配列番号13の塩基配列における26番目の塩基（rs1081022の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q14)　配列番号14の塩基配列における26番目の塩基（rs1648835の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q15)　配列番号15の塩基配列における26番目の塩基（rs12144738の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q16)　配列番号16の塩基配列における26番目の塩基（rs1494320の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q17)　配列番号17の塩基配列における26番目の塩基（rs1712674の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q18)　配列番号18の塩基配列における26番目の塩基（rs1418425の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q19)　配列番号19の塩基配列における26番目の塩基（rs4688637の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q20)　配列番号20の塩基配列における26番目の塩基（rs12374531の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q21)　配列番号21の塩基配列における26番目の塩基（rs11784415の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q22)　配列番号22の塩基配列における26番目の塩基（rs2182093の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q23)　配列番号23の塩基配列における26番目の塩基（rs10798の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q24)　配列番号24の塩基配列における26番目の塩基（rs4267316の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q25)　配列番号25の塩基配列における26番目の塩基（rs6071980の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q26)　配列番号26の塩基配列における26番目の塩基（rs743057の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q27)　配列番号27の塩基配列における26番目の塩基（rs1178938の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q28)　配列番号28の塩基配列における26番目の塩基（rs800065の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q29)　配列番号29の塩基配列における26番目の塩基（rs1372667の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q30)　配列番号30の塩基配列における26番目の塩基（rs13174549の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q31)　配列番号31の塩基配列における26番目の塩基（rs7087410の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q32)　配列番号32の塩基配列における26番目の塩基（rs10898382の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q33)　配列番号33の塩基配列における26番目の塩基（rs951729の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q34)　配列番号34の塩基配列における26番目の塩基（rs1658693の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q35)　配列番号35の塩基配列における26番目の塩基（rs1820920の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q36)　配列番号36の塩基配列における26番目の塩基（rs11737270の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q37)　配列番号37の塩基配列における26番目の塩基（rs10832678の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
(q38)　配列番号38の塩基配列における26番目の塩基（rs10507084の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ;又は
(q39)　配列番号39の塩基配列における26番目の塩基（rs1440548の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ。
[７]　[５]のプライマー又は[６]のプローブを含む、結核症を発症するリスクを判定するためのキット。
[８]　被験体において、結核症の発症と関連している被験体ゲノムの一塩基多型部位の近傍に位置する遺伝子の発現量を測定し、かつ被験体に潜伏感染している結核菌遺伝系統をタイピングし、被験体において潜伏感染している結核菌により結核症を発症するリスクを判定する方法。
[９]　被験体が感染している結核菌が非北京株であるときに、配列番号16で示される塩基配列の26番目の塩基における一塩基多型（(nb2)　rs1494320）の近傍に位置する遺伝子であるCD53遺伝子の発現を測定し、該遺伝子の発現が上昇している場合に、結核症の発症のリスクが高いと判定する、[８]の方法。
[１０]　被験体が感染している結核菌が非北京株であるときに、配列番号25で示される塩基配列の26番目の塩基における一塩基多型（(nb11)　rs6071980）の近傍に位置する遺伝子であるMAFB遺伝子の発現を測定し、該遺伝子の発現が上昇している場合に、結核症の発症のリスクが高いと判定する、[８]の方法。
　本明細書は本願の優先権の基礎となる日本国特許出願番号2017-150296号の開示内容を包含する。 That is, the present invention is as follows.
[1] In the subject, identify the base of the single nucleotide polymorphism site of the subject's human genome that is associated with the onset of tuberculosis, and type the latent infection of the subject with the T. tuberculosis genetic line, and the subject Method for determining the risk of developing tuberculosis in a Mycobacterium tuberculosis genetic lineage-specifically by Mycobacterium tuberculosis latently infected in
[2] The method of [1], wherein the M. tuberculosis genetic line to be typed is selected from the group consisting of Beijing strain, non-Beijing strain, EAI strain and non-EAI strain.
[3] When the M. tuberculosis species with which the subject is infected is a Beijing strain, the base of at least one single nucleotide polymorphism site of the following (b1) to (b14) is identified, and the subject is infected: When the tubercle bacillus is a non-Beijing strain, the base of at least one single nucleotide polymorphism site of (nb1) to (nb12) below is identified, and the tubercle bacillus infecting the subject is the strain EAI Sometimes, the base of at least one single nucleotide polymorphism site of the following (e1) to (e8) is identified, and the Mycobacterium tuberculosis with which the subject is infected is a non-EAI strain, the following (ne1) The method of [1] or [2], comprising identifying a base of at least one single nucleotide polymorphism site of (ne5):
(b1) rs9348878
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 1, G or A;
(b2) rs2070600
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 2, which is A or G;
(b3) rs401864
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 3, C or T;
(b4) rs673119
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 4 and is C or T;
(b5) rs1321267
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 5, which is C or A;
(b6) rs2076625
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 6, which is G or T;
(b7) rs7142055
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 7 and T or C;
(b8) rs1157619
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 8 and T or C;
(b9) rs4924568
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 9 and is A or G;
(b10) rs1899820
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 10, which is A or C;
(b11) rs2695163
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 11, G or A;
(b12) rs1197772
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 12 and G or A;
(b13) rs1081022
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 13 and T or G;
(b14) rs 1648835
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 14 and T or G;
(nb1) rs12144738
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 15, C or T;
(nb2) rs1494320
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 16, which is C or T;
(nb3) rs1712674
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 17, G or T;
(nb4) rs1418425
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 18, which is T or C;
(nb5) rs4688637
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 19 and is C or A;
(nb6) rs12374531
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 20, which is G or A;
(nb7) rs11784415
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 21, which is C or A;
(nb8) rs2182093
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 22, which is T or C;
(nb9) rs10798
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 23, which is A or G;
(nb10) rs4267316
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 24, C or T;
(nb11) rs6071980
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 25 and is C or T;
(nb12) rs743057
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 26, which is A or G;
(e1) rs1178938
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 27 and is C or A;
(e2) rs800065
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 28 and is C or T;
(e3) rs1372667
Polymorphism at base 26 of the base sequence shown in SEQ ID NO: 29, G or T;
(e4) rs13174549
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 30, which is T or C;
(e5) rs7087410
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 31, which is C or T;
(e6) rs10898382
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 32, and is A or C;
(e7) rs951729
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 33, which is A or C;
(e8) rs1658693
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 34, which is C or T;
(ne1) rs1820920
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 35, which is C or T;
(ne2) rs11737270
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 36, which is G or A; (ne3) rs10832678
Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 37, which is G or A;
(ne4) rs10507084
Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 38, T or C; or
(ne5) rs1440548
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 39, which is C or T.
[4] (1) When the base of the 26th single nucleotide polymorphism site ((b1) rs9348878) of the base sequence shown in SEQ ID NO: 1 is G, in the younger period (less than 45 years of age) compared with A Determined that the risk of developing tuberculosis is high,
(2) When the base of the 26th single nucleotide polymorphism site ((b2) rs2070600) of the base sequence shown in SEQ ID NO: 2 is A, tuberculosis is younger than in the case of G (at less than 45 years of age) It is judged that the risk of developing is high,
(3) When the base of the 26th single nucleotide polymorphism site ((b3) rs401864) of the base sequence shown in SEQ ID NO: 3 is C, the risk of developing tuberculosis at any age is higher than in the case of T Determined as
(4) When the base of the 26th single nucleotide polymorphism site ((b4) rs673119) of the base sequence shown in SEQ ID NO: 4 is C, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is high,
(5) When the base of the 26th single nucleotide polymorphism site ((b5) rs1321267) of the base sequence shown in SEQ ID NO: 5 is C, tuberculosis is younger than in the case of A (less than 45 years of age) It is judged that the risk of developing is high,
(6) When the base of the 26th single nucleotide polymorphism site ((b6) rs2076625) of the nucleotide sequence shown in SEQ ID NO: 6 is G, the risk of developing tuberculosis at any age is lower than in T. Determined as
(7) When the base of the 26th single nucleotide polymorphism site ((b7) rs7142055) of the base sequence shown in SEQ ID NO: 7 is T, tuberculosis is younger than in the case of C (less than 45 years of age) It is judged that the risk of developing is high,
(8) When the base of the 26th single nucleotide polymorphism site ((b8) rs1157619) of the base sequence shown in SEQ ID NO: 8 is T, the risk of developing tuberculosis at any age is higher than in the case of C Determined as
(9) When the base of the 26th single nucleotide polymorphism site ((b9) rs4924568) of the base sequence shown in SEQ ID NO: 9 is A, tuberculosis is observed in old age (45 years or older) compared to G. It is judged that the risk of developing is high,
(10) When the base of the 26th single nucleotide polymorphism site ((b10) rs1899820) of the base sequence shown in SEQ ID NO: 10 is A, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
(11) When the base of the 26th single nucleotide polymorphism site ((b11) rs2695163) of the base sequence shown in SEQ ID NO: 11 is G, tuberculosis is observed in old age (45 years or older) as compared with A. It is judged that the risk of developing is high,
(12) When the base of the 26th single nucleotide polymorphism site ((b12) rs1197772) of the base sequence shown in SEQ ID NO: 12 is G, tuberculosis is observed in old age (45 years or older) as compared with A. It is judged that the risk of developing is high,
(13) When the base of the 26th single nucleotide polymorphism site ((b13) rs1081022) of the base sequence shown in SEQ ID NO: 13 is T, tuberculosis is observed in old age (45 years or older) compared to G. It is judged that the risk of developing is high,
(14) When the base of the 26th single nucleotide polymorphism site ((b14) rs 1648835) of the base sequence shown in SEQ ID NO: 14 is T, tuberculosis is detected in old age (45 years or older) compared to G. It is judged that the risk of developing is high,
(15) When the base of the 26th single nucleotide polymorphism site ((nb1) rs12144738) of the base sequence shown in SEQ ID NO: 15 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
(16) When the base of the 26th single nucleotide polymorphism site ((nb2) rs1494320) of the base sequence shown in SEQ ID NO: 16 is C, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is high,
(17) When the base of the 26th single nucleotide polymorphism site ((nb3) rs1712674) of the base sequence shown in SEQ ID NO: 17 is G, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is high,
(18) When the base of the 26th single nucleotide polymorphism site ((nb 4) rs 1418425) of the base sequence shown by SEQ ID NO: 18 is T, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
(19) When the base of the 26th single nucleotide polymorphism site ((nb5) rs4688637) of the base sequence shown in SEQ ID NO: 19 is C, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
(20) Tuberculosis in old age (more than 45 years old) compared to the case of A when the base of the 26th single nucleotide polymorphism site ((nb6) rs12374531) of the base sequence shown in SEQ ID NO: 20 is G It is judged that the risk of developing is low.
(21) When the base of the 26th single nucleotide polymorphism site ((nb7) rs11784415) of the base sequence shown by SEQ ID NO: 21 is C, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
(22) When the base of the 26th single nucleotide polymorphism site ((nb8) rs2182093) of the base sequence shown in SEQ ID NO: 22 is T, tuberculosis is younger than in the case of C (less than 45 years of age) It is judged that the risk of developing is high,
(23) When the base of the 26th single nucleotide polymorphism site ((nb9) rs10798) of the base sequence shown by SEQ ID NO: 23 is A, the risk of developing tuberculosis at any age is higher than in the case of G Determined as
(24) When the 26th single nucleotide polymorphism site ((nb 10) rs 4267 316) of the nucleotide sequence shown in SEQ ID NO: 24 is C, the risk of developing tuberculosis at any age is higher than in T. Determined as
(25) When the base of the 26th single nucleotide polymorphism site ((nb11) rs6071980) of the base sequence shown by SEQ ID NO: 25 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
(26) When the base of the 26th single nucleotide polymorphism site ((nb12) rs743057) of the nucleotide sequence shown in SEQ ID NO: 26 is A, the risk of developing tuberculosis at any age is lower than in the case of G Determined as
(27) When the base of the 26th single nucleotide polymorphism site ((e1) rs1178938) of the base sequence shown in SEQ ID NO: 27 is C, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
(28) When the base of the 26th single nucleotide polymorphism site ((e2) rs8000065) of the base sequence shown in SEQ ID NO: 28 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
(29) When the base of the 26th single nucleotide polymorphism site ((e3) rs1372667) in the nucleotide sequence shown in SEQ ID NO: 29 is G, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
(30) When the base of the 26th single nucleotide polymorphism site ((e4) rs13174549) of the nucleotide sequence shown in SEQ ID NO: 30 is T, the risk of developing tuberculosis at any age is lower than in the case of C Determined as
(31) When the base of the 26th single nucleotide polymorphism site ((e5) rs7087410) of the base sequence shown in SEQ ID NO: 31 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
(32) When the base of the 26th single nucleotide polymorphism site ((e6) rs10898382) of the base sequence shown in SEQ ID NO: 32 is A, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
(33) When the base of the 26th single nucleotide polymorphism site ((e7) rs951729) of the base sequence shown in SEQ ID NO: 33 is A, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
(34) When the base of the 26th single nucleotide polymorphism site ((e8) rs1658693) of the base sequence shown in SEQ ID NO: 34 is C, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is low.
(35) When the base of the 26th single nucleotide polymorphism site ((ne1) rs1820920) of the base sequence shown in SEQ ID NO: 35 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
(36) When the base of the 26th single nucleotide polymorphism site ((ne2) rs11737270) of the base sequence shown in SEQ ID NO: 36 is G, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
(37) When the base of the 26th single nucleotide polymorphism site ((ne3) rs10832678) of the nucleotide sequence shown in SEQ ID NO: 37 is G, tuberculosis is detected in old age (45 years or older) as compared with A. It is judged that the risk of developing is high,
(38) When the base of the 26th single nucleotide polymorphism site ((ne4) rs10507084) of the nucleotide sequence shown in SEQ ID NO: 38 is T, tuberculosis is observed in old age (45 years or older) compared to C. Determined that the risk of developing is low, or
(39) When the base of the 26th single nucleotide polymorphism site ((ne5) rs1440548) of the nucleotide sequence shown in SEQ ID NO: 39 is C, the risk of developing tuberculosis at any age is higher than in the case of T To determine
Method of [3].
[5] A primer for human genome for determining the risk of developing tuberculosis in a M. tuberculosis-infected subject, which is a risk of developing tuberculosis in a Beijing strain-infected subject according to any of the following (p1) to (p14): A primer for determining the risk, a primer for determining the risk of developing tuberculosis in a non-Beijing strain-infected subject according to any of the following (p15) to (p26), any of the following (p27) to (p34): Primers for determining the risk of developing tuberculosis in any EAI strain infected subject, or for determining the risk of developing tuberculosis in a non-EAI infected subject having any of the following (p35) to (p39) Primer:
(p1) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs9348878) in the base sequence of SEQ ID NO: 1;
(p2) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs2070600) in the nucleotide sequence of SEQ ID NO: 2;
(p3) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs401864) in the base sequence of SEQ ID NO: 3;
(p4) a primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs673119) in the base sequence of SEQ ID NO: 4;
(p5) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1321267) in the base sequence of SEQ ID NO: 5;
(p6) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs2076625) in the base sequence of SEQ ID NO: 6;
(p7) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs7142055) in the nucleotide sequence of SEQ ID NO: 7;
(p8) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1157619) in the nucleotide sequence of SEQ ID NO: 8;
(p9) A primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs4924568) in the base sequence of SEQ ID NO: 9;
(p10) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1899820) in the base sequence of SEQ ID NO: 10;
(p11) a primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs2695163) in the base sequence of SEQ ID NO: 11;
(p12) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1197772) in the nucleotide sequence of SEQ ID NO: 12;
(p13) a primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1081022) in the nucleotide sequence of SEQ ID NO: 13;
(p14) A primer capable of amplifying a region containing the 26th base (a base at polymorphic site of rs1648835) in the nucleotide sequence of SEQ ID NO: 14;
(p15) A primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs12144738) in the nucleotide sequence of SEQ ID NO: 15;
(p16) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16;
(p17) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1712674) in the nucleotide sequence of SEQ ID NO: 17
(p18) A primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1418425) in the nucleotide sequence of SEQ ID NO: 18;
(p19) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs4688637) in the nucleotide sequence of SEQ ID NO: 19;
(p20) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs12374531) in the nucleotide sequence of SEQ ID NO: 20;
(p21) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs11784415) in the nucleotide sequence of SEQ ID NO: 21;
(p22) a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs2182093) in the nucleotide sequence of SEQ ID NO: 22;
(p23) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs10798) in the base sequence of SEQ ID NO: 23;
(p24) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs4267316) in the nucleotide sequence of SEQ ID NO: 24;
(p25) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs6071980) in the nucleotide sequence of SEQ ID NO: 25;
(p26) A primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs743057) in the nucleotide sequence of SEQ ID NO: 26;
(p27) a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27;
(p28) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs8000065) in the nucleotide sequence of SEQ ID NO: 28;
(p29) A primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1372667) in the nucleotide sequence of SEQ ID NO: 29;
(p30) A primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs13174549) in the nucleotide sequence of SEQ ID NO: 30;
(p31) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs7087410) in the base sequence of SEQ ID NO: 31;
(p32) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs10898382) in the nucleotide sequence of SEQ ID NO: 32;
(p33) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs951729) in the base sequence of SEQ ID NO: 33;
(p34) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1658693) in the nucleotide sequence of SEQ ID NO: 34;
(p35) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1820920) in the nucleotide sequence of SEQ ID NO: 35;
(p36) a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs11737270) in the nucleotide sequence of SEQ ID NO: 36;
(p37) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10832678) in the nucleotide sequence of SEQ ID NO: 37;
(p38) a primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs10507084) in the base sequence of SEQ ID NO: 38; or
(p39) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1440548) in the nucleotide sequence of SEQ ID NO: 39.
[6] A probe for determining the risk of developing tuberculosis in a T. tuberculosis-infected subject, comprising
A probe for determining the risk of developing tuberculosis in a Beijing strain-infected subject according to any of the following (q1) to (q14), a non-Beijing strain-infected subject according to any of the following (q15) to (q26): A probe for determining the risk of developing tuberculosis or a probe for determining the risk of developing tuberculosis in a subject infected with any of the EAI strains described in (q27) to (q34) below or (q35) A probe for determining the risk of developing tuberculosis in a non-EAI strain-infected subject of any of (q39): (q1) the 26th base in the base sequence of SEQ ID NO: 1 (base at polymorphic site of rs9348878) A probe capable of hybridizing to a region comprising
(q2) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 2 (the base of polymorphic site of rs2070600);
(q3) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 3 (a base of polymorphic site of rs401864);
(q4) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs673119) in the base sequence of SEQ ID NO: 4;
(q5) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1321267) in the base sequence of SEQ ID NO: 5;
(q6) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs2076625) in the base sequence of SEQ ID NO: 6;
(q7) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 7 (a base at polymorphic site of rs7142055);
(q8) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1157619) in the base sequence of SEQ ID NO: 8;
(q9) a probe capable of hybridizing to a region including the 26th base (a base at a polymorphic site of rs4924568) in the base sequence of SEQ ID NO: 9;
(q10) a probe capable of hybridizing to a region containing the 26th base (a base at polymorphic site of rs1899820) in the base sequence of SEQ ID NO: 10;
(q11) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs2695163) in the nucleotide sequence of SEQ ID NO: 11;
(q12) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs1197772) in the base sequence of SEQ ID NO: 12;
(q13) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1081022) in the base sequence of SEQ ID NO: 13;
(q14) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1648835) in the base sequence of SEQ ID NO: 14;
(q15) a probe capable of hybridizing to a region including the 26th base (a base at a polymorphic site of rs12144738) in the base sequence of SEQ ID NO: 15;
(q16) a probe capable of hybridizing to a region including the 26th base (a base at a polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16;
(q17) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1712674) in the base sequence of SEQ ID NO: 17;
(q18) a probe capable of hybridizing to a region containing the 26th base in the base sequence of SEQ ID NO: 18 (a base at polymorphic site of rs1418425);
(q19) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs4688637) in the base sequence of SEQ ID NO: 19;
(q20) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs12374531) in the nucleotide sequence of SEQ ID NO: 20;
(q21) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 21 (a base at polymorphic site of rs11784415);
(q22) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 22 (the base of polymorphic site of rs2182093);
(q23) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs10798) in the base sequence of SEQ ID NO: 23;
(q24) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 24 (a base at a polymorphic site of rs4267316);
(q25) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs6071980) in the base sequence of SEQ ID NO: 25;
(q26) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs743057) in the base sequence of SEQ ID NO: 26;
(q27) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27;
(q28) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 28 (the base of polymorphic site of rs8000065);
(q29) a probe capable of hybridizing to a region containing the 26th base (a base at polymorphic site of rs1372667) in the base sequence of SEQ ID NO: 29;
(q30) a probe capable of hybridizing to a region containing a 26th base (a base at a polymorphic site of rs13174549) in the base sequence of SEQ ID NO: 30;
(q31) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs7087410) in the nucleotide sequence of SEQ ID NO: 31;
(q32) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10898382) in the nucleotide sequence of SEQ ID NO: 32;
(q33) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs951729) in the base sequence of SEQ ID NO: 33;
(q34) a probe capable of hybridizing to a region containing a 26th base (a base at a polymorphic site of rs1658693) in the base sequence of SEQ ID NO: 34;
(q35) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs1820920) in the base sequence of SEQ ID NO: 35;
(q36) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 36 (a base at polymorphic site of rs11737270);
(q37) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10832678) in the base sequence of SEQ ID NO: 37;
(q38) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10507084) in the base sequence of SEQ ID NO: 38; or
(q39) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs 1440548) in the base sequence of SEQ ID NO: 39.
[7] A kit for determining the risk of developing tuberculosis, comprising the primer of [5] or the probe of [6].
[8] In a subject, the expression level of a gene located in the vicinity of a single nucleotide polymorphism site of the subject genome which is associated with the onset of tuberculosis is measured, and a latent infection of Mycobacterium tuberculosis A method of typing strains to determine the risk of developing tuberculosis due to a latently infected M. tuberculosis in a subject.
[9] When the tubercle bacillus in which the subject is infected is a non-Beijing strain, it is located in the vicinity of a single nucleotide polymorphism ((nb2) rs1494320) at the 26th base of the nucleotide sequence shown in SEQ ID NO: 16 The method according to [8], wherein the expression of the gene CD53 gene is measured, and if the expression of the gene is elevated, the risk of developing tuberculosis is determined to be high.
[10] When the M. tuberculosis species with which the subject is infected is a non-Beijing strain, it is located in the vicinity of a single nucleotide polymorphism ((nb11) rs6071980) at the 26th base of the nucleotide sequence shown in SEQ ID NO: 25 The method according to [8], wherein the expression of the gene MAFB is measured to determine that the risk of developing tuberculosis is high if the expression of the gene is elevated.
The present specification includes the disclosure content of Japanese Patent Application No. 2017-150296 based on which the priority of the present application is based.
　本発明の方法により、一塩基多型を同定し、又はその一塩基多型部位の近傍遺伝子の発現を測定することにより、結核菌に感染している結核菌の遺伝系統ごとに、結核症の発症リスクを判定し、結核症の発症のリスクが高い結核菌感染者を未発症の感染者の中から効率的に選別し、発症前に治療を行い、発症を未然に防ぐことができる。 According to the method of the present invention, a single nucleotide polymorphism is identified, or the expression of a gene adjacent to the single nucleotide polymorphism site is measured, whereby it is possible to use tuberculosis for each genetic line of M. tuberculosis infected with M. tuberculosis. It is possible to determine the risk of onset and efficiently sort out M. tuberculosis-infected persons who are at high risk of onset of tuberculosis from uninfected persons, treat them before onset, and prevent onset.
結核菌遺伝系統特異的に結核症の発症と関連した一塩基多型のリスト及び近傍の遺伝子を示す図である（北京株）。It is a figure which shows the list | wrist of the single nucleotide polymorphism specifically related to the onset of the tuberculosis, and the gene of the vicinity of M. tuberculosis gene lineage specifically (Beijing strain). 結核菌遺伝系統特異的に結核症の発症と関連した一塩基多型のリスト及び近傍の遺伝子を示す図である（北京株）（図１－１の続き）。FIG. 7 shows a list of single nucleotide polymorphisms specifically associated with the onset of tuberculosis and genes in the vicinity (specifically, Beijing strain) of M. tuberculosis genetic lineage (the continuation of FIG. 1-1). 結核菌遺伝系統特異的に結核症の発症と関連した一塩基多型のリスト及び近傍の遺伝子を示す図である（非北京株）。It is a figure which shows the list | wrist of the single nucleotide polymorphism specifically related to the onset of the tuberculosis and the gene of the vicinity (specifically, non-Beijing strain). 結核菌遺伝系統特異的に結核症の発症と関連した一塩基多型のリスト及び近傍の遺伝子を示す図である（非北京株）（図２－１の続き）。FIG. 2 shows a list of single nucleotide polymorphisms specifically associated with the onset of tuberculosis and genes in the vicinity (specifically, non-Beijing strain) of M. tuberculosis genetic lineage (continuation of FIG. 2-1). 結核菌遺伝系統特異的に結核症の発症と関連した一塩基多型のリスト及び近傍の遺伝子を示す図である（EAI株）。It is a figure which shows the list | wrist of the single nucleotide polymorphism specifically related to the onset of the tuberculosis, and the gene of the vicinity of M. tuberculosis inheritance specifically (EAI strain). 結核菌遺伝系統特異的に結核症の発症と関連した一塩基多型のリスト及び近傍の遺伝子を示す図である（非EAI株）。It is a figure which shows the list | wrist of the single nucleotide polymorphism specifically related to the tuberculosis onset, and the gene of the vicinity with M. tuberculosis inheritance (non-EAI strain). 結核発症リスク候補遺伝子であるCD53遺伝子の結核患者における発現解析の結果を示す図である。It is a figure which shows the result of the expression analysis in the tuberculosis patient of the CD53 gene which is a candidate gene for risk of developing tuberculosis. 結核発症リスク候補遺伝子であるMAFB遺伝子の結核患者における発現解析の結果を示す図である。It is a figure which shows the result of the expression analysis in the tuberculosis patient of the MAFB gene which is a candidate for a tuberculosis onset risk gene.
　以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本発明はヒト及び結核菌の遺伝子情報に基づいて、被験体の結核症（TB: Tuberculosis）発症のリスクを判定する方法である。ここで、被験体の結核症発症のリスクを判定するとは、被験体における結核症の発症のし易さ、又はしにくさを判定することをいう。本発明において、結核菌(Mycobacterium tuberculosis）に感染しているが発症していない被験体、すなわち、結核菌が潜伏感染している被験体を対象とする。また、本発明は、被験体の結核症発症のリスクを判定するための補助的データを取得する方法でもある。本発明において、評価、判定とは予測ともいう。 The present invention is a method for determining the risk of developing tuberculosis (TB) in a subject based on human and M. tuberculosis genetic information. Here, determining the risk of developing tuberculosis in a subject refers to determining the likelihood or difficulty of developing tuberculosis in a subject. In the present invention, a subject infected with, but not developing Mycobacterium tuberculosis, is a subject that is latently infected with Mycobacterium tuberculosis. The present invention is also a method of obtaining ancillary data to determine the risk of developing tuberculosis in a subject. In the present invention, evaluation and determination are also referred to as prediction.
　結核症とは、結核菌により引き起こされる感染症をいう。好発部位は肺であるが、全身の臓器、器官に感染し、肺結核あるいは結核性髄膜炎、結核性リンパ節炎等の肺外結核を発症する。 Tuberculosis refers to an infectious disease caused by Mycobacterium tuberculosis. The most common site is lung, but it infects organs and organs throughout the body and causes extrapulmonary tuberculosis such as pulmonary tuberculosis or tuberculosis meningitis, tuberculosis lymphadenitis.
　世界中のヒトのうち３人に１人は結核菌に感染している。結核菌に感染しているヒトのうち、結核症を発症するヒトは10人に１人程度である。また、発症するヒトでも感染から10年～数十年経てから発症することも多い。本発明の方法で、結核症発症のリスクを判定し、リスクが高いと判定された場合、予め結核菌に対する抗生物質を投与することにより発症を回避することができる。 One in three people in the world is infected with M. tuberculosis. Among humans infected with tuberculosis, about 1 in 10 people develop tuberculosis. In addition, even in the case of developing humans, it often develops 10 to several decades after infection. According to the method of the present invention, the risk of developing tuberculosis can be determined, and if it is determined that the risk is high, the onset can be avoided by administering an antibiotic against M. tuberculosis in advance.
　具体的には、潜伏感染している被験体における結核症の発症のし易さと関連しているヒトゲノム上のSNP（一塩基多型）を分析し、一塩基多型部位の塩基の種類に基づいて結核症発症のリスクを評価、判定する。ここで、一塩基多型の分析とは、一塩基多型部位の塩基を同定することをいう。 Specifically, SNPs (single nucleotide polymorphisms) on the human genome that are associated with susceptibility to development of tuberculosis in latently infected subjects are analyzed, and based on the type of base at the single nucleotide polymorphism site. Assess and assess the risk of developing tuberculosis. Here, analysis of single nucleotide polymorphism means identifying a base at a single nucleotide polymorphism site.
　また、結核症の発症のし易さと関連している一塩基多型部位の近傍に位置する遺伝子の発現を測定し、該発現量に基づいて結核症発症のリスクを評価、判定する。一塩基多型部位の近傍に位置する遺伝子は、一塩基多型部位に距離的に近い遺伝子、好ましくは距離的に最も近い遺伝子をいう。一塩基多型部位の近傍に位置する遺伝子は、一塩基多型部位のアリルにより、発現が減退したり、発現が亢進したりする。従って、一塩基多型部位の近傍に位置する遺伝子の発現を測定することにより、一塩基多型部位の塩基を指標に結核症発症のリスクを判定できるのと同様に、結核症の発症のし易さと関連している一塩基多型部位の近傍に位置する遺伝子の発現を指標に結核症発症のリスクを判定することができる。 In addition, the expression of a gene located in the vicinity of a single nucleotide polymorphism site associated with the susceptibility to development of tuberculosis is measured, and the risk of developing tuberculosis is evaluated and determined based on the expression amount. The gene located in the vicinity of the single nucleotide polymorphism site refers to a gene that is close in distance to the single nucleotide polymorphism site, preferably the gene that is the closest in distance. The gene located in the vicinity of the single nucleotide polymorphism site is reduced in expression or enhanced in expression by the allele at the single nucleotide polymorphism site. Therefore, by measuring the expression of a gene located in the vicinity of the single nucleotide polymorphism site, it is possible to determine the onset of tuberculosis as it is possible to determine the risk of developing tuberculosis using the base of the single nucleotide polymorphism site as an index. The risk of developing tuberculosis can be determined using the expression of a gene located in the vicinity of the single nucleotide polymorphism site associated with susceptibility.
　結核菌ゲノムの遺伝系統(Lineage)は多様性を示し、北京（Beijing）株、EAI（East-African Indian)株、CAS（Central Asian Strain)株、Euro-American株等がある。また、北京株は感染者が多いため、北京株以外の株をまとめて非北京（非Beijing）株と呼び、非北京株にはEAI株、CAS株及びEuro-American株が含まれる。同様に、EAI株は感染者が多いため、EAI株以外の株をまとめて非EAI株と呼び、非EAI株には北京株、CAS株及びEuro-American株が含まれる。 The genetic lineage (Lineage) of the tubercle bacillus genome shows diversity, such as Beijing (Beijing) strain, EAI (East-African Indian) strain, CAS (Central Asian Strain) strain, Euro-American strain and the like. In addition, since Beijing strains are often infected, non-Beijing strains are collectively referred to as non-Beijing strains, and non-Beijing strains include EAI strains, CAS strains and Euro-American strains. Similarly, since the EAI strain is frequently infected, strains other than the EAI strain are collectively referred to as non-EAI strains, and non-EAI strains include Beijing strains, CAS strains and Euro-American strains.
　潜伏感染している結核菌の株により、被験体における結核症発症のリスクと関連する一塩基多型は異なる。さらに、被験体の年齢により結核症発症のリスクは異なっており、年齢により老年性発症又は若年性発症という。発症する被験体の年齢が４５歳以上のときに老年性発症といい、４５歳未満のときに若年性発症という（Mahasirimongkol S et al. J Hum Genet. 2012 Jun;57(6):363-7）。 Depending on the strain of latently infected M. tuberculosis, the single nucleotide polymorphisms associated with the risk of developing tuberculosis in a subject are different. Furthermore, the risk of developing tuberculosis varies with the age of the subject, and is referred to as senile or juvenile onset depending on the age. A subject who develops onset is said to be senile onset when the age of the subject is 45 years or older, and that it is juvenile onset when the age is under 45 (Mahasirimongkol S et al. J Hum Genet. 2012 Jun; 57 (6): 363-7 ).
　実際に結核症を発症した患者から結核菌を単離し、タイピングにより結核菌の遺伝系統を決定するとともに、該患者のゲノム全域の一塩基多型を分析する。この際、ヒトのゲノム全域の一塩基多型情報を用いた主成分分析を実施することにより、関連解析を実施する前に収集した患者から健常者群と同様の遺伝的背景を持つ患者群を抽出することが可能となる。また、患者の発症年齢情報を考慮することで、共通の発症機構を有していると考えられる患者群を抽出することが可能となる。 Mycobacterium tuberculosis is isolated from a patient who has actually developed tuberculosis, and the genetic lineage of Mycobacterium tuberculosis is determined by typing, and single nucleotide polymorphisms across the patient's genome are analyzed. At this time, by performing principal component analysis using single nucleotide polymorphism information of the entire human genome, patients collected from before the association analysis are compared with a group of patients having a genetic background similar to the group of healthy people. It becomes possible to extract. Also, by considering the onset age information of the patients, it is possible to extract a group of patients considered to have a common onset mechanism.
　そのような方法で抽出した患者群を用いて、感染している結核菌のゲノム情報をもとに、北京株感染患者群、非北京株感染患者群、EAI株感染患者群、非EAI株感染患者群それぞれに結核症全患者群を分類し、共通の遺伝系統の結核菌に感染した患者群と健常者群における各一塩基多型のアリル頻度を比較する関連解析を実施することで、結核菌の遺伝系統の感染時の発症と特異的な関連を有する一塩基多型を同定することができる。 Using a group of patients extracted by such a method, based on the genome information of infected tuberculosis bacteria, a group of patients infected with Beijing strain, a group of patients infected with non-Beijing strain, a group of patients infected with EAI strain, non-EAI strain infection By classifying the whole patient group of tuberculosis for each patient group and performing association analysis to compare the allele frequency of each single nucleotide polymorphism in the patient group infected with the common genetic strain of tuberculosis and the healthy subject group It is possible to identify single nucleotide polymorphisms that have a specific relationship with the onset of infection of a genetic line of the fungus.
　本発明者らは、ヒト全ゲノム解析（GWAS)の手法により、ヒトゲノム上の複数の一塩基多型が結核の発症と関連していることを見出し、本発明を完成させたが、ここで結核の発症と関連しているとは、一塩基多型のアリルと結核症を発症するリスクとが統計学的に関連していることをいう。 The present inventors have found that multiple single nucleotide polymorphisms on the human genome are associated with the onset of tuberculosis by the method of human whole genome analysis (GWAS), and completed the present invention. Is associated with the occurrence of a single nucleotide polymorphism of allyl and the risk of developing tuberculosis statistically related.
　一塩基多型の分析は、一塩基多型部位の塩基の種類、すなわちアリルを決定することをいい、１対の染色体上の一方の染色体について検出する場合も、両方の染色体について検出する場合も包含され、両方の染色体について検出する場合にも、一塩基多型部位においてホモ接合性かヘテロ接合性かの検出を含む。被験体から単離した試料に含まれる特定のアリルに対立する各々のアリルを検出し、遺伝子型を決定することができる。あるアリルのみが検出された場合は当該アリルをホモに有するホモ接合性であり、２つのアリルが検出された場合には該２つのアリルをヘテロに有するヘテロ接合性である。 Analysis of single nucleotide polymorphisms refers to determining the type of base at single nucleotide polymorphism site, ie, allyl, whether it is detected for one chromosome on a pair of chromosomes or for both chromosomes. Inclusion, detection for both chromosomes also includes detection of homozygosity or heterozygosity at the single nucleotide polymorphism site. Each allele that is opposite to a particular allele contained in a sample isolated from a subject can be detected and genotyped. When only one allyl is detected, it is homozygous having the allele homozygously, and when two allyls are detected, it is heterozygous having the two alleles heterozygously.
　結核菌が潜伏感染している被験体における、結核症の発症のリスクは以下の方法で判定する。 The risk of developing tuberculosis in a subject with latent infection with M. tuberculosis is determined by the following method.
　被験体の結核菌感染部位より、結核菌を単離する。通常は被験体の喀痰から単離すればよい。結核菌の単離のため、結核患者の喀痰をLowenstein-Jensen培地に塗布し、37℃で4～6週間培養する。培養された菌体からゲノムDNAを抽出する。具体的な抽出方法としては、菌体をTE(10mM Tris HCl pH 8.0, 1mM EDTA)に懸濁後、80℃20分の熱処理により殺菌し、10mg/mlのリゾチーム溶液を添加し、一晩反応させることで溶菌させる。さらに10%SDS/proteinase K溶液を添加し65℃10分の反応後、5M NaCl及びCTAB/NaCl溶液を添加し、さらに65℃10分反応させる。その後、クロロフォルム/イソアミルアルコール溶液と混合し、水層に対して2-プロパノールを用いてDNA沈殿を行う。70%エタノールで洗浄後、残ったペレットをTEバッファーに懸濁し、DNA濃度を測定する。 Mycobacterium tuberculosis is isolated from the site of Mycobacterium tuberculosis infection in the subject. Usually, it may be isolated from the subject's sputum. For isolation of M. tuberculosis, the sputum of M. tuberculosis patient is applied to Lowenstein-Jensen medium and cultured at 37 ° C. for 4 to 6 weeks. Genomic DNA is extracted from the cultured cells. As a specific extraction method, after suspending the cells in TE (10 mM Tris HCl pH 8.0, 1 mM EDTA), kill by heat treatment at 80 ° C. for 20 minutes, add 10 mg / ml lysozyme solution, and react overnight Let it be lysed. After addition of 10% SDS / proteinase K solution and reaction at 65 ° C. for 10 minutes, 5 M NaCl and CTAB / NaCl solution are added, and reaction is further conducted at 65 ° C. for 10 minutes. Thereafter, it is mixed with a chloroform / isoamyl alcohol solution, and the aqueous layer is subjected to DNA precipitation using 2-propanol. After washing with 70% ethanol, the remaining pellet is suspended in TE buffer, and the DNA concentration is measured.
　単離した結核菌ゲノムDNAをタイピングし、遺伝系統を決定する。結核菌をタイピングするためのマーカー及び方法は公知であり、例えば、特定のマーカーの存非をPCR法により測定するGagneux S et al. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2869-73.に記載のLSP（Large Sequence Polymorphism）判定法や、本発明者らが開発したDigiTag2法を結核菌ゲノムのSNPタイピングに応用した判定法（Srilohasin P et al. J. Clin. Microbiol. 2014, 52(6): 1962-8)で行うことができる。LSP判定法とは具体的には、EAI株、北京株、CAS株、Euro-American株に分類する場合は、マーカーとなるゲノム領域として、RD239、TbD1、RD105、RD750、7bp deletion at pks 15/1の５つを組み合わせて用いる。特異的なプライマーセットにより対象領域を増幅することで、その増幅産物のサイズにより対象領域の欠失の有無を判定し、遺伝系統の判定が出来る。EAI株はRD239(-)かつTbD1（＋）であり、北京株はRD105(-)かつTbD1(-)であり、CAS株はRD750(-)かつTbD1(-)であり、Euro-American株はTbD1(-)かつ7bp deletion at pks 15/1である。 The isolated M. tuberculosis genomic DNA is typed to determine the genetic lineage. Markers and methods for typing M. tuberculosis are known, and for example, Gagneux S et al. Proc Natl Acad Sci USA A. 2006 Feb 21; 103 (8) which measures the presence or absence of a specific marker by PCR. J. Clin. Microbiol: A method of determining the Large Sequence Polymorphism (LSP) described in 2869-73. Or the DigiTag 2 method developed by the present inventors for SNP typing of the tuberculosis genome (Srilohasin P et al. J. Clin. Microbiol 2014, 52 (6): 1962-8). Specifically, when the LSP determination method is classified into EAI strain, Beijing strain, CAS strain and Euro-American strain, RD239, TbD1, RD105, RD750, 7 bp deletion at pks 15 / as a genomic region to be a marker. It uses combining 5 of 1. By amplifying the target region with a specific primer set, the presence or absence of the deletion of the target region can be determined by the size of the amplification product, and the genetic line can be determined. EAI strain is RD239 (-) and TbD1 (+), Beijing strain is RD105 (-) and TbD1 (-), CAS strain is RD750 (-) and TbD1 (-), Euro-American strain is TbD1 (-) and 7 bp deletion at pks 15/1.
　これらのタイピング方法は一例である。結核菌遺伝系統は、上記の遺伝系統の分類だけでなく、さらに亜系統に分類できる。より細分類して、それぞれの系統について、結核症発症に関連した一塩基多型を決定することもできる。 These typing methods are an example. The M. tuberculosis genetic line can be further classified into sublines as well as the above-mentioned classification of genetic lines. It is also possible to further subdivide and determine single nucleotide polymorphisms associated with the onset of tuberculosis for each strain.
　結核菌のタイピングと同時に、被験体の末梢血細胞よりゲノムを抽出し、一塩基多型を分析するか、あるいは、一塩基多型部位の近傍に位置する遺伝子の発現量を測定すればよい。発現量は例えば、血液中の発現量を測定すればよい。すなわち、本発明においては、被験体に潜伏感染している結核菌を採取し、タイピングし結核菌の遺伝系統を決定し、同時に被験体のヒトゲノム中の結核症の発症のし易さと関連している一塩基多型を分析し、又は該一塩基多型の近傍に位置する遺伝子の発現量を測定する。最終的に感染している結核菌の型ごとに、被験体の一塩基多型分析又は遺伝子の発現量から、結核症発症のリスクを判定する。 At the same time as typing of M. tuberculosis, the genome may be extracted from peripheral blood cells of the subject and single nucleotide polymorphisms may be analyzed, or the expression amount of a gene located in the vicinity of the single nucleotide polymorphism site may be measured. For the expression level, for example, the expression level in blood may be measured. That is, in the present invention, M. tuberculosis which is latently infected in the subject is collected, and typing is performed to determine the genetic lineage of M. tuberculosis, and at the same time, in relation to the susceptibility to development of tuberculosis in the human genome of the subject. The single nucleotide polymorphism is analyzed, or the expression level of the gene located in the vicinity of the single nucleotide polymorphism is measured. The risk of developing tuberculosis is determined from single nucleotide polymorphism analysis or gene expression level of the subject for each type of finally infected M. tuberculosis.
　具体的には、本発明の方法においては、それぞれ、北京株感染被験体、非北京株感染被験体、EAI株感染被験体、及び非EAI株感染被験体について以下の一塩基多型を分析する。一塩基多型を示す「rsXXXXXX（Ｘは任意の数字）」は、NCBI(National Center for Biotechnology Information)のSNPデータベース(dbSNP BUILD137)のリファレンス番号であるrs番号を示す。 Specifically, in the method of the present invention, the following single nucleotide polymorphisms are analyzed for a Beijing strain-infected subject, a non-Beijing strain-infected subject, an EAI strain-infected subject, and a non-EAI strain-infected subject, respectively. . “RsXXXXXX (X is an arbitrary number)” indicating a single nucleotide polymorphism indicates an rs number which is a reference number of a SNP database (dbSNP BUILD 137) of NCBI (National Center for Biotechnology Information).
　以下の一塩基多型は、特定の遺伝系統の結核菌に感染時の結核症の発症との関連をP値で表した場合に、1×10-5以下の一塩基多型である。ここで、P値とは結核症を発症した患者群と発症しない健常者群とで一塩基多型の頻度に差があるかどうかを示す値であり、値が小さいほど、相関が確からしいと判定される。 The following single nucleotide polymorphism is a single nucleotide polymorphism of 1 × 10 −5 or less when it is expressed as P value in relation to the onset of tuberculosis at the time of infection with M. tuberculosis of a specific genetic strain. Here, the P value is a value indicating whether there is a difference in the frequency of single nucleotide polymorphisms between the group of patients who developed tuberculosis and the group of healthy people who do not develop tuberculosis, and the smaller the value, the more likely the correlation is. It is judged.
　また、一塩基多型部位の塩基は、SNPデータベースに登録されている順鎖又は逆鎖いずれかの配列における塩基で表している。他方の鎖の配列では、相補的な塩基となる。 In addition, the base at the single nucleotide polymorphism site is represented by a base in either the normal strand or reverse strand sequence registered in the SNP database. In the sequence of the other strand, they are complementary bases.
北京株感染被験体
rs9348878、rs2070600、rs401864、rs673119、rs1321267、rs2076625、rs7142055、rs1157619、rs4924568、rs1899820、rs2695163、rs1197772、rs1081022、rs1648835 Beijing stock infected subject
rs9348878, rs2070600, rs401864, rs673119, rs1321267, rs2076625, rs7142055, rs1157619, rs4924568, rs1899820, rs2695163, rs1197772, rs1081022, rs1648835
非北京株感染被験体
rs12144738、rs1494320、rs1712674、rs1418425、rs4688637、rs12374531、rs11784415、rs2182093、rs10798、rs4267316、rs6071980、rs743057 Non-Beijing Strain-Infected Subjects
rs12144738, rs1494320, rs1712674, rs1418425, rs4688637, rs12374531, rs11784415, rs2182093, rs10798, rs4267316, rs6071980, rs743057
EAI株感染被験体
rs1178938、rs800065、rs1372667、rs13174549、rs7087410、rs10898382、rs951729、rs1658693 EAI strain infected subject
rs1178938, rs800065, rs1372667, rs13174549, rs7087410, rs10898382, rs951729, rs1658693
非EAI株感染被験体
rs1820920、rs11737270、rs10832678、rs10507084、rs1440548 Non-EAI strain infected subject
rs1820920, rs11737270, rs10832678, rs10507084, rs1440548
　上記rs番号で表される一塩基多型は以下に説明する一塩基多型である。以下の説明において、それぞれの一塩基多型において、特定の結核菌遺伝系統の発症のリスクの大きさを示すオッズ比（OR)(95％信頼区間）、及びP値を示す。ある一塩基多型のオッズ比が１以上の場合その一塩基多型においてマイナーアリルを有する被験体は結核症を発症する可能性が高くなる。例えば、1.94の場合、結核症を発症する可能性は、1.94倍に高まる。一方、ある一塩基多型のオッズ比が１未満の場合その一塩基多型においてマイナーアリルを有する被験体は結核症を発症する可能性が低くなる。例えば、0.61の場合、結核症を発症する可能性は、0.61倍に低下する。 The single nucleotide polymorphism represented by the above rs number is a single nucleotide polymorphism described below. In the following description, in each single nucleotide polymorphism, odds ratio (OR) (95% confidence interval) indicating the magnitude of risk of development of a specific M. tuberculosis genetic line is shown, and P value. When the odds ratio of a single nucleotide polymorphism is 1 or more, a subject having a minor allele at the single nucleotide polymorphism is more likely to develop tuberculosis. For example, in the case of 1.94, the probability of developing tuberculosis increases by 1.94 times. On the other hand, when the odds ratio of a single nucleotide polymorphism is less than 1, a subject having minor alleles in the single nucleotide polymorphism is less likely to develop tuberculosis. For example, at 0.61, the probability of developing tuberculosis decreases 0.61 times.
北京株感染被験体
(b1)　rs9348878
　配列番号１で示される塩基配列の26番目の塩基における多型であり、G又はAである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.98 (1.48-2.64)であり、P値は、2.69×10-6である。 Beijing stock infected subject
(b1) rs9348878
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 1 is G or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying A allele. The odds ratio is 1.98 (1.48-2.64) and the P value is 2.69 × 10 -6 .
(b2)　rs2070600
　配列番号２で示される塩基配列の26番目の塩基における多型であり、A又はGである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がAの場合に、Gの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてGアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.00 (1.50-2.67)であり、P値は、2.07×10-6である。 (b2) rs2070600
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 2 is A or G. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of G. That is, it can be determined that the risk of developing tuberculosis at a younger age (less than 45 years old) is higher in a subject carrying A allele (minor allele) than a subject carrying G allele. The odds ratio is 2.00 (1.50-2.67) and the P value is 2.07 × 10 −6 .
(b3)　rs401864
　配列番号３で示される塩基配列の26番目の塩基における多型であり、C又はTである。一塩基多型部位の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.63 (1.32-2.02)であり、P値は、5.36×10-6である。 (b3) rs401864
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 3 is C or T. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of T. That is, it can be determined that in subjects carrying C allele (minor allele) there is a higher risk of developing tuberculosis at any age than subjects carrying T allele. The odds ratio is 1.63 (1.32-2.02) and the P value is 5.36 × 10 −6 .
(b4)　rs673119
　配列番号４で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.80 (1.39-2.33)であり、P値は、6.97×10-6である。 (b4) rs673119
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 4 is C or T. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of T. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis in old age (45 or older) than a subject who holds T allele. The odds ratio is 1.80 (1.39-2.33) and the P value is 6.97 × 10 −6 .
(b5)　rs1321267
　配列番号５で示される塩基配列の26番目の塩基における多型であり、C又はAである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.95 (1.46-2.60)であり、P値は、5.35×10-6である。 (b5) rs1321267
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 5 is C or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele. The odds ratio is 1.95 (1.46-2.60) and the P value is 5.35 × 10 −6 .
(b6)　rs2076625
　配列番号６で示される塩基配列の26番目の塩基における多型であり、G又はTである。一塩基多型部位の塩基がGの場合に、Tの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に小さい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが低いと判定することができる。オッズ比は、0.61 (0.49-0.75)であり、P値は、4.31×10-6である。 (b6) rs2076625
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 6 is G or T. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis at any age is significantly smaller than in the case of T. That is, it can be determined that the risk of developing tuberculosis at any age is lower in subjects carrying G allele (minor allele) than subjects carrying T allele. The odds ratio is 0.61 (0.49-0.75) and the P value is 4.31 × 10 −6 .
(b7)　rs7142055
　配列番号７で示される塩基配列の26番目の塩基における多型であり、T又はCである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.08 (1.50-2.89)であり、P値は、7.78×10-6である。 (b7) rs7142055
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 7 is T or C. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying C-allyl. The odds ratio is 2.08 (1.50-2.89) and the P value is 7.78 × 10 −6 .
(b8)　rs1157619
　配列番号８で示される塩基配列の26番目の塩基における多型であり、T又はCである。一塩基多型部位の塩基がTの場合に、Cの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に大きい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.49 (1.70-3.64)であり、P値は、1.27×10-6である。 (b8) rs1157619
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 8 is T or C. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allyl) is at a higher risk of developing tuberculosis at any age than a subject carrying C-allyl. The odds ratio is 2.49 (1.70-3.64) and the P value is 1.27 × 10 −6 .
(b9)　rs4924568
　配列番号９で示される塩基配列の26番目の塩基における多型であり、A又はGである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がAの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてGアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.31 (1.60-3.35)であり、P値は、5.15×10-6である。 (b9) rs4924568
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 9 is A or G. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of G. That is, it can be determined that a subject who holds A allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than a subject who holds G allele. The odds ratio is 2.31 (1.60-3.35) and the P value is 5.15 × 10 −6 .
(b10)　rs1899820
　配列番号10で示される塩基配列の26番目の塩基における多型であり、A又はCである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.31 (1.60-3.35)であり、P値は、5.15×10-6である。 (b10) rs1899820
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 10, which is A or C. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of C. That is, it can be determined that a subject who holds A allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than a subject who holds C allele. The odds ratio is 2.31 (1.60-3.35) and the P value is 5.15 × 10 −6 .
(b11)　rs2695163
　配列番号11で示される塩基配列の26番目の塩基における多型であり、G又はAである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.35 (1.63-3.38)であり、P値は、2.97×10-6である。 (b11) rs2695163
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 11 is G or A. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying A allele. The odds ratio is 2.35 (1.63-3.38) and the P value is 2.97 × 10 −6 .
(b12)　rs1197772
　配列番号12で示される塩基配列の26番目の塩基における多型であり、G又はAである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.36 (1.64-3.40)であり、P値は、2.02×10-6である。 (b12) rs1197772
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 12 is G or A. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying A allele. The odds ratio is 2.36 (1.64-3.40) and the P value is 2.02 × 10 −6 .
(b13)　rs1081022
　配列番号13で示される塩基配列の26番目の塩基における多型であり、T又はGである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がTの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてGアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.27 (1.62-3.18)であり、P値は、9.83×10-7である。 (b13) rs1081022
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 13 is T or G. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of G. That is, it can be determined that the subject carrying T allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying G allele. The odds ratio is 2.27 (1.62-3.18) and the P value is 9.83 × 10 -7 .
(b14)　rs1648835
　配列番号14で示される塩基配列の26番目の塩基における多型であり、T又はGである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がTの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてGアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.33 (1.65-3.29)であり、P値は、8.60×10-7である。 (b14) rs 1648835
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 14 and is T or G. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of G. That is, it can be determined that the subject carrying T allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying G allele. The odds ratio is 2.33 (1.65-3.29) and the P value is 8.60 × 10 −7 .
非北京株感染被験体
(nb1)　rs12144738
　配列番号15で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.22 (1.59-3.10)であり、P値は、2.08×10-6である。 Non-Beijing Strain-Infected Subjects
(nb1) rs12144738
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 15, and is C or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.22 (1.59-3.10) and the P value is 2.08 × 10 −6 .
(nb2)　rs1494320
　配列番号16で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.71 (1.40-2.08)であり、P値は、7.84×10-8である。 (nb2) rs1494320
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 16 is C or T. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of T. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis in old age (45 or older) than a subject who holds T allele. The odds ratio is 1.71 (1.40-1.08) and the P value is 7.84 × 10 −8 .
(nb3)　rs1712674
　配列番号17で示される塩基配列の26番目の塩基における多型であり、G又はTである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.77 (1.40-2.25)であり、P値は、1.63×10-6である。 (nb3) rs1712674
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 17 is G or T. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of T. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in the old age (45 years or older) than a subject carrying T allele. The odds ratio is 1.77 (1.40-2.25) and the P value is 1.63 × 10 −6 .
(nb4)　rs1418425
　配列番号18で示される塩基配列の26番目の塩基における多型であり、T又はCである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.74 (1.43-2.12)であり、P値は、2.54×10-8である。 (nb4) rs1418425
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 18 is T or C. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying C-allyl. The odds ratio is 1.74 (1.43-2.12) and the P value is 2.54 × 10 −8 .
(nb5)　rs4688637
　配列番号19で示される塩基配列の26番目の塩基における多型であり、C又はAである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.08 (1.50-2.88)であり、P値は、7.15×10-6である。 (nb5) rs4688637
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 19 and is C or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele. The odds ratio is 2.08 (1.50-2.88) and the P value is 7.15 × 10 −6 .
(nb6)　rs12374531
　配列番号20で示される塩基配列の26番目の塩基における多型であり、G又はAである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Aの場合に比べ結核症老年期（４５歳以上）において結核症を発症する被験体の割合が有意に小さい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが低いと判定することができる。オッズ比は、0.58 (0.45-0.74)であり、P値は、8.54×10-6である。 (nb6) rs12374531
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 20, which is G or A. This single nucleotide polymorphism is highly associated with senile onset. In the case where the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis in the old age of tuberculosis (45 years old or older) is significantly smaller than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a lower risk of developing tuberculosis in old age (45 years old or older) than the subject carrying A allele. The odds ratio is 0.58 (0.45-0.74) and the P value is 8.54 × 10 −6 .
(nb7)　rs11784415
　配列番号21で示される塩基配列の26番目の塩基における多型であり、C又はAである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.03 (1.50-2.74)であり、P値は、2.54×10-6である。 (nb7) rs11784415
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 21 and is C or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele. The odds ratio is 2.03 (1.52 to 2.74) and the P value is 2.54 × 10 −6 .
(nb8)　rs2182093
　配列番号22で示される塩基配列の26番目の塩基における多型であり、T又はCである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.38 (1.65-3.43)であり、P値は、1.80×10-6である。 (nb8) rs2182093
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 22 is T or C. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of C. That is, it can be determined that a subject carrying T-allyl (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying C-allyl. The odds ratio is 2.38 (1.65 to 4.43) and the P value is 1.80 × 10 -6 .
(nb9)　rs10798
　配列番号23で示される塩基配列の26番目の塩基における多型であり、A又はGである。一塩基多型部位の塩基がAの場合に、Gの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に大きい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてGアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.60 (1.32-1.95)であり、P値は、2.31×10-6である。 (nb9) rs10798
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 23, and is A or G. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of G. That is, it can be determined that a subject who carries A allele (minor allele) is at higher risk of developing tuberculosis at any age than a subject who carries G allele. The odds ratio is 1.60 (1.32-1.95) and the P value is 2.31 × 10 −6 .
(nb10)　rs4267316
　配列番号24で示される塩基配列の26番目の塩基における多型であり、C又はTである。一塩基多型部位の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.26 (1.58-3.23)であり、P値は、5.29×10-6である。 (nb10) rs4267316
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 24 is C or T. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of T. That is, it can be determined that in subjects carrying C allele (minor allele) there is a higher risk of developing tuberculosis at any age than subjects carrying T allele. The odds ratio is 2.26 (1.58-32) and the P value is 5.29 × 10 −6 .
(nb11)　rs6071980
　配列番号25で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.09 (1.51-2.90)であり、P値は、6.77×10-6である。 (nb11) rs6071980
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 25 and is C or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.09 (1.51-2.90) and the P value is 6.77 × 10 −6 .
(nb12)　rs743057
　配列番号26で示される塩基配列の26番目の塩基における多型であり、A又はGである。一塩基多型部位の塩基がAの場合に、Gの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に小さい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてGアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが低いと判定することができる。オッズ比は、0.59 (0.47-0.74)であり、P値は、5.70×10-6である。 (nb12) rs743057
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 26 is A or G. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis at any age is significantly smaller than in the case of G. That is, it can be determined that the risk of developing tuberculosis at any age is lower in subjects carrying A allele (minor allele) than in subjects carrying G allele. The odds ratio is 0.59 (0.47-0.74) and the P value is 5.70 × 10 −6 .
EAI株感染被験体
(e1)　rs1178938
　配列番号27で示される塩基配列の26番目の塩基における多型であり、C又はAである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.37 (1.67-3.35)であり、P値は、5.97×10-7である。 EAI strain infected subject
(e1) rs1178938
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 27 and is C or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject who holds C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject who holds A allele. The odds ratio is 2.37 (1.67-3.35) and the P value is 5.97 × 10 -7 .
(e2)　rs800065
　配列番号28で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.33 (1.65-3.30)であり、P値は、9.72×10-7である。 (e2) rs800065
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 28 is C or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.33 (1.65-3.30) and the P value is 9.72 × 10 −7 .
(e3)　rs1372667
　配列番号29で示される塩基配列の26番目の塩基における多型であり、G又はTである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.29 (1.59-3.32)であり、P値は、6.43×10-6である。 (e3) rs1372667
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 29, and is G or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of T. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.29 (1.59-3.32) and the P value is 6.43 × 10 −6 .
(e4)　rs13174549
　配列番号30で示される塩基配列の26番目の塩基における多型であり、T又はCである。一塩基多型部位の塩基がTの場合に、Cの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に小さい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが低いと判定することができる。オッズ比は、0.44 (0.31-0.62)であり、P値は、2.02×10-6である。 (e4) rs13174549
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 30, and is T or C. When the base at the single nucleotide polymorphism site is T, the proportion of subjects who develop tuberculosis at any age is significantly smaller than in the case of C. That is, it can be determined that the subject carrying T allele (minor allele) has a lower risk of developing tuberculosis at any age than a subject carrying C allele. The odds ratio is 0.44 (0.31-0.62) and the P value is 2.02 × 10 −6 .
(e5)　rs7087410
　配列番号31で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.27 (1.58-3.25)であり、P値は、5.94×10-6である。 (e5) rs7087410
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 31, and is C or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.27 (1.58-3.25) and the P value is 5.94 × 10 −6 .
(e6)　rs10898382
　配列番号32で示される塩基配列の26番目の塩基における多型であり、A又はCである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.62 (1.32-2.00)であり、P値は、3.66×10-6である。 (e6) rs10898382
It is a polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 32, and is A or C. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of C. That is, it can be determined that a subject who holds A allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than a subject who holds C allele. The odds ratio is 1.62 (1.32-2.00) and the P value is 3.66 × 10 −6 .
(e7)　rs951729
　配列番号33で示される塩基配列の26番目の塩基における多型であり、A又はCである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Aアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.61 (1.31-1.97)であり、P値は、5.93×10-6である。 (e7) rs951729
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 33, which is A or C. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is A, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly larger than in the case of C. That is, it can be determined that a subject who holds A allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than a subject who holds C allele. The odds ratio is 1.61 (1.31-1.97) and the P value is 5.93 × 10 -6 .
(e8)　rs1658693
　配列番号34で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に小さい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが低いと判定することができる。オッズ比は、0.63 (0.51-0.77)であり、P値は、8.57×10-6である。 (e8) rs1658693
The polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 34, which is C or T. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis in old age (45 years or older) is significantly smaller than in the case of T. That is, it can be determined that a subject who holds C allele (minor allele) has a lower risk of developing tuberculosis in old age (45 years or older) than a subject who holds T allele. The odds ratio is 0.63 (0.51-0.77) and the P value is 8.57 × 10 −6 .
非EAI株感染被験体
(ne1)　rs1820920
　配列番号35で示される塩基配列の26番目の塩基における多型であり、C又はTである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、2.04 (1.48-2.82)であり、P値は、9.18×10-6である。 Non-EAI strain infected subject
(ne1) rs1820920
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 35, which is C or T. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly greater than in the case of T. That is, it can be determined that a subject carrying C allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying T allele. The odds ratio is 2.04 (1.48-2.82) and the P value is 9.18 × 10 −6 .
(ne2)　rs11737270
　配列番号36で示される塩基配列の26番目の塩基における多型であり、G又はAである。この一塩基多型は、若年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも若年期（４５歳未満）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.81 (1.40-2.34)であり、P値は、4.14×10-6である。 (ne2) rs11737270
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 36, which is G or A. This single nucleotide polymorphism is highly associated with juvenile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis at a young age (less than 45 years old) is significantly larger than in the case of A. That is, it can be determined that a subject carrying G allele (minor allele) has a higher risk of developing tuberculosis at a younger age (less than 45 years old) than a subject carrying A allele. The odds ratio is 1.81 (1.40-1.34) and the P value is 4.14 × 10 −6 .
(ne3)　rs10832678
　配列番号37で示される塩基配列の26番目の塩基における多型であり、G又はAである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に大きい。すなわち、Gアリル(マイナーアリル）を保有している被験体においてAアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.66 (1.33-2.07)であり、P値は、5.66×10-6である。 (ne3) rs10832678
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 37, which is G or A. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is G, the proportion of subjects who develop tuberculosis in the old age (45 years or older) is significantly larger than in the case of A. That is, it can be determined that the subject carrying G allele (minor allele) has a higher risk of developing tuberculosis in old age (45 years or older) than the subject carrying A allele. The odds ratio is 1.66 (1.33-2.07) and the P value is 5.66 × 10 −6 .
(ne4)　rs10507084
　配列番号38で示される塩基配列の26番目の塩基における多型であり、T又はCである。この一塩基多型は、老年性発症との関連性が高い。一塩基多型部位の塩基がTの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症する被験体の割合が有意に小さい。すなわち、Tアリル(マイナーアリル）を保有している被験体においてCアリルを保有している被験体よりも老年期（４５歳以上）において結核症を発症するリスクが低いと判定することができる。オッズ比は、0.58 (0.46-0.73)であり、P値は、4.21×10-6である。 (ne4) rs10507084
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 38, which is T or C. This single nucleotide polymorphism is highly associated with senile onset. When the base at the single nucleotide polymorphism site is T, the percentage of subjects who develop tuberculosis in old age (45 years or older) is significantly smaller than in the case of C. That is, it can be determined that the subject carrying T-allyl (minor allele) has a lower risk of developing tuberculosis in old age (45 years old or older) than the subject carrying C-allyl. The odds ratio is 0.58 (0.46-0.73) and the P value is 4.21 × 10 −6 .
(ne5)　rs1440548
　配列番号39で示される塩基配列の26番目の塩基における多型であり、C又はTである。一塩基多型部位の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症する被験体の割合が有意に大きい。すなわち、Cアリル(マイナーアリル）を保有している被験体においてTアリルを保有している被験体よりもあらゆる年齢において結核症を発症するリスクが高いと判定することができる。オッズ比は、1.70 (1.35-2.13)であり、P値は、4.12×10-6である。 (ne5) rs1440548
The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 39, which is C or T. When the base at the single nucleotide polymorphism site is C, the proportion of subjects who develop tuberculosis at any age is significantly greater than in the case of T. That is, it can be determined that in subjects carrying C allele (minor allele) there is a higher risk of developing tuberculosis at any age than subjects carrying T allele. The odds ratio is 1.70 (1.35-2.13) and the P value is 4.12 x 10-6 .
　被験体が感染している結核菌が北京株であるときに、上記の(b1)～(b14)の少なくとも１つ、好ましくは２、３、４、５、６、７、８、９、10、11、12、13又は14個の塩基を同定し、被験体が感染している結核菌が非北京株であるときに、上記の(nb1)～(nb12)の少なくとも１つ、好ましくは２、３、４、５、６、７、８、９、10、11又は12個の一塩基多型部位の塩基を同定し、被験体が感染している結核菌がEAI株であるときに、上記の(e1)～(e8)の少なくとも１つ、好ましくは２、３、４、５、６、７又は８個の一塩基多型部位の塩基を同定し、被験体が感染している結核菌が非EAI株であるときに、上記の(ne1)～(ne5)の少なくとも１つ、好ましくは２、３、４又は5個の一塩基多型部位の塩基を同定し、塩基の種類により結核症を発症するリスクを判定することができる。 When the Mycobacterium tuberculosis with which the subject is infected is a Beijing strain, at least one of (b1) to (b14) above, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 bases, and at least one of (nb1) to (nb12) above, preferably 2 when the M. tuberculosis strain with which the subject is infected is a non-Beijing strain. , 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 single nucleotide polymorphism site bases are identified, and when the tubercle bacillus from which the subject is infected is the EAI strain, Tuberculosis which identifies a base of at least one, preferably 2, 3, 4, 5, 6, 7 or 8 single nucleotide polymorphic sites of the above (e1) to (e8) and which is infected with the subject When the strain is a non-EAI strain, at least one, preferably 2, 3, 4 or 5 single nucleotide polymorphism site bases of the above (ne1) to (ne5) are identified, and the types of bases To determine the risk of developing tuberculosis It is possible.
　また、上記一塩基多型の分析の代りに、あるいは、一塩基多型の分析と共に、被験体における一塩基多型部位の近傍に位置する遺伝子の発現を測定してもよい。該遺伝子の発現が亢進しているか、叉は減弱している場合に、前記被験体が結核症を発症するリスクが高いと判定することができる。 Also, instead of the above single nucleotide polymorphism analysis, or together with the single nucleotide polymorphism analysis, expression of a gene located near the single nucleotide polymorphism site in the subject may be measured. When the expression of the gene is enhanced or diminished, it can be determined that the subject is at high risk of developing tuberculosis.
　上記の一塩基多型は人類集団によらず存在するため、本発明の方法は世界中のあらゆる人類集団に適用することができる。本発明の方法においては、一塩基多型の分析と結核菌のタイピングを同時に行うが、人類集団によっては、感染している結核菌が１種類の場合があり、このような場合は、タイピングを省略してもよい。例えば、日本人はほとんどが北京型である。 The method of the present invention can be applied to all human groups in the world because the single nucleotide polymorphisms described above do not exist in human groups. In the method of the present invention, analysis of single nucleotide polymorphism and typing of M. tuberculosis are performed simultaneously, but depending on the human population, there may be one type of M. tuberculosis infected, and in such a case, It may be omitted. For example, most Japanese are of the Beijing type.
　上記の各一塩基多型部位の近傍に位置する遺伝子は以下のとおりである。
北京株感染被験体
rs9348878　PRRT1（Proline Rich Transmembrane Protein 1) (6.8kbp 3')
rs2070600　AGER (Advanced Glycosylation End-product specific Receptor) (Missense)
rs401864　ASCC3 (Activating Signal Cointegrator 1 Complex subunit 3) (Intron)
rs673119　ASCC3 (Activating Signal Cointegrator 1 Complex subunit 3) (43kbp 5')rs1321267　LOC100507254 (Intron)
rs2076625　KIAA1549L (KIAA1549 Like) (Intron)
rs7142055　MIS18BP1 (MIS18 Binding Protein 1) (264kbp 3')
rs1157619　MEIS2 (Meis homeobox 2) (Intron)
rs4924568　MGA (MGA, MAX dimerization protein) (4.6kbp 5’)
rs1899820　MGA (MGA, MAX dimerization protein) (1.0kbp 5’)
rs2695163　MGA (MGA, MAX dimerization protein) (Synonymous)
rs1197772　MAPKBP1 (Mitogen-Activated Protein Kinase Binding Protein 1) (2.1kbp 5')
rs1081022　MAPKBP1 (Mitogen-Activated Protein Kinase Binding Protein 1) (Intron)rs1648835　JMJD7-PLA2G4B (Jumonji Domain containing 7 and Phospholipase A2, Group IVB) (Intron) The genes located in the vicinity of each single nucleotide polymorphism site described above are as follows.
Beijing stock infected subject
rs9348878 PRRT1 (Proline Rich Transmembrane Protein 1) (6.8 kbp 3 ')
rs2070600 AGER (Advanced Glycosylation End-product specific Receptor) (Missense)
rs401864 ASCC3 (Activating Signal Cointegrator 1 Complex subunit 3) (Intron)
rs673119 ASCC3 (Activating Signal Cointegrator 1 Complex subunit 3) (43 kbp 5 ') rs1321267 LOC100507254 (Intron)
rs2076625 KIAA1549L (KIAA1549 Like) (Intron)
rs7142055 MIS18BP1 (MIS18 Binding Protein 1) (264 kbp 3 ')
rs1157619 MEIS2 (Meis homeobox 2) (Intron)
rs4924568 MGA (MGA, MAX dimerization protein) (4.6 kbp 5 ')
rs1899820 MGA (MGA, MAX dimerization protein) (1.0 kbp 5 ')
rs2695163 MGA (MGA, MAX dimerization protein) (Synonymous)
rs1197772 MAPKBP1 (Mitogen-Activated Protein Kinase Binding Protein 1) (2.1 kbp 5 ')
rs1081022 MAPKBP1 (Mitogen-Activated Protein Kinase Binding Protein 1) (Intron) rs1648835 JMJD7-PLA2G4B (Jumonji Domain containing 7 and Phospholipase A2 Group IVB)
非北京株感染被験体
rs12144738　FHAD1 (Forkhead Associated phosphopeptide binding Domain 1) (Intron)rs1494320　CD53 (Intron)
rs1712674　CD53 (23kbp 3')
rs1418425　LRIF1 (Ligand dependent nuclear Receptor Interacting Factor 1) (21kbp 3')
rs4688637　PTPRG (Protein Tyrosine Phosphatase, Receptor type G) (Intron)
rs12374531　PPP2R2B (Protein Phosphatase 2 Regulatory subunit Bbeta) (52kbp 5')rs11784415　LRRC69 (Leucine Rich Repeat Containing 69) (Intron)
rs2182093　PLCE1 (Phospholipase C Epsilon 1) (Intron)
rs10798　KCNQ1 (Potassium voltage-gated channel subfamily Q member 1) (3'-UTR)
rs4267316　MAF (MAF bZIP transcription factor) (268kbp 5')
rs6071980　MAFB (MAF bZIP transcription factor B) (446kbp 3')
rs743057　FAM19A5 (Family with sequence similarity 19 member A5, C-C motif chemokine like) (Intron) Non-Beijing Strain-Infected Subjects
rs12144738 FHAD1 (Forkhead Associated Phosphate binding Domain 1) (Intron) rs1494320 CD53 (Intron)
rs1712674 CD53 (23 kbp 3 ')
rs1418425 LRIF1 (Ligand dependent nuclear Receptor Interacting Factor 1) (21 kbp 3 ')
rs4688637 PTPRG (Protein Tyrosine Phosphatase, Receptor type G) (Intron)
rs12374531 PPP2R2B (Protein Phosphatase 2 Regulatory subunit Bbeta) (52 kbp 5 ') rs11784415 LRRC69 (Leucine Rich Repeat Containing 69) (Intron)
rs2182093 PLCE1 (Phospholipase C Epsilon 1) (Intron)
rs10798 KCNQ1 (Potassium voltage-gated channel subfamily Q member 1) (3'-UTR)
rs 4267 316 MAF (MAF bZIP transcription factor) (268 kbp 5 ')
rs6071980 MAFB (MAF bZIP transcription factor B) (446 kbp 3 ')
rs743057 FAM19A5 (Family with sequence similarity 19 member A5, CC motif like) (Intron)
EAI株感染被験体
rs1178938　C3orf58 (Chromosome 3 open reading frame 58) (67kbp 3')
rs800065　C3orf58 (Chromosome 3 open reading frame 58) (68kbp 3')
rs1372667　CDH12 (Cadherin 12) (31kbp 5')
rs13174549　EBF1 (Early B-cell Factor 1) (Intron)
rs7087410　LOC220906 (106kbp 3')
rs10898382　DLG2 (Discs Large MAGUK scaffold protein 2) (Intron)
rs951729　DLG2 (Discs Large MAGUK scaffold protein 2) (Intron)
rs1658693　BTG1 (BTG anti-proliferation factor 1) (26kbp 5') EAI strain infected subject
rs1178938 C3orf 58 (Chromosome 3 open reading frame 58) (67 kbp 3 ')
rs800065 C3orf 58 (Chromosome 3 open reading frame 58) (68 kbp 3 ')
rs1372667 CDH12 (Cadherin 12) (31 kbp 5 ')
rs13174549 EBF1 (Early B-cell Factor 1) (Intron)
rs7087410 LOC220906 (106 kbp 3 ')
rs10898382 DLG2 (Discs Large MAGUK scaffold protein 2) (Intron)
rs951729 DLG2 (Discs Large MAGUK scaffold protein 2) (Intron)
rs1658693 BTG1 (BTG anti-proliferation factor 1) (26 kbp 5 ')
非EAI株感染被験体
rs1820920　MIR4790 (MicroRNA 4790) (301kbp 5')
rs11737270　FBXW7 (F-box and WD repeat domain containing 7) (254kbp 3')
rs10832678　C11orf58 (Chromosome 11 open reading frame 58) (7.9kbp 3')
rs10507084　RMST (Rhabdomyosarcoma 2 associated transcript) (106kbp 5')
rs1440548　LOC284294 (450kbp 3') Non-EAI strain infected subject
rs 1820920 MIR 4790 (MicroRNA 4790) (301 kbp 5 ')
rs11737270 FBXW7 (F-box and WD repeat domain containing 7) (254 kbp 3 ')
rs10832678 C11orf 58 (Chromosome 11 open reading frame 58) (7.9 kbp 3 ')
rs10507084 RMST (Rhabdoyosarcoma 2 associated transcript) (106 kbp 5 ')
rs 1440548 LOC284294 (450 kbp 3 ')
　上記の遺伝子のうち、CD53の発現が非北京株感染被験体において、健常者に比べて上昇した場合に、該被験体は結核症発症のリスクが高いと判定することができる。また、MAFBの発現が非北京株感染被験体において、健常者に比べて上昇した場合に、該被験体は結核症発症のリスクが高いと判定することができる。 When the expression of CD53 among the above genes is elevated in a non-Beijing strain-infected subject as compared to a healthy subject, it can be determined that the subject is at high risk of developing tuberculosis. In addition, when the expression of MAFB is elevated in a non-Beijing strain-infected subject as compared to a healthy subject, it can be determined that the subject is at high risk of developing tuberculosis.
　図１－１及び図１－２に上記の一塩基多型のrs番号、一塩基多型が存在するヒト染色体の番号、マイナーアリル/メジャーアリル、一塩基多型の近傍に位置する遺伝子、発症が老年期か若年期か、結核菌各遺伝系統のP値、及びオッズ比を示す。 1-1 and 1-2 show the rs number of the single nucleotide polymorphism, the number of the human chromosome where the single nucleotide polymorphism exists, minor allele / major allele, genes located in the vicinity of the single nucleotide polymorphism, onset Shows the P value and odds ratio of each tubercle bacillus genetic line whether it is old age or young age.
　本発明において、上記の一塩基多型及び該一塩基多型部位の近傍に位置する遺伝子は、結核症を発症するリスクを判定するための遺伝子マーカーということができる。 In the present invention, the above single nucleotide polymorphism and the gene located in the vicinity of the single nucleotide polymorphism site can be referred to as a gene marker for determining the risk of developing tuberculosis.
　本発明の方法においては、被験体から試料を採取し、該検体のDNAやRNAについて一塩基多型を分析すればよい。すなわち、被験体から一塩基多型を含むゲノムDNAを抽出し、抽出したDNAに含まれる対立遺伝子の一塩基多型部位の塩基を同定すればよい。　分析に用いる検体としては、染色体DNAを含む試料ならばあらゆる試料を用いることができ、例えば、血液、皮膚、口腔粘膜、毛、尿、爪、細胞等が挙げられる。これらの試料から、常法に従い、染色体、DNA又はRNA等の核酸を単離し分析すればよい。 In the method of the present invention, a sample may be collected from a subject and single nucleotide polymorphisms may be analyzed for DNA and RNA of the sample. That is, genomic DNA containing single nucleotide polymorphisms may be extracted from a subject, and bases of single nucleotide polymorphism sites of alleles contained in the extracted DNA may be identified. As a sample used for analysis, any sample can be used as long as it is a sample containing chromosomal DNA, and examples thereof include blood, skin, oral mucosa, hair, urine, nails, cells and the like. From these samples, nucleic acids such as chromosomes, DNA or RNA may be isolated and analyzed according to a conventional method.
　一塩基多型の解析は、通常の遺伝子多型解析方法によって行うことができる。例えば、ジデオキシ法やMaxam-Gilbert法等の公知の方法により直接配列決定するシークエンス解析による解析法、遺伝子多型に特異的なプローブや該プローブを固定化したマイクロアレイ（DNAチップ）などを用いるハイブリダイゼーション法、遺伝子多型に特異的なプライマーを用いる種々の方法などがあげられ、さらに具体的に、プライマー伸長法（TaqMan（登録商標）法）、PCR-SSCP法、一本鎖コンフォメーション多型解析（SSCP;single strand conformation polymorphism）、Invader法、シングルヌクレオチドプライマー法、PCR法、NASBA法、LCR法、SDA法、LAMP法、制限断片長多型（RFLP）を利用する方法、変性勾配ゲル電気泳動法（DGGE）、ミスマッチ部位の化学的切断を利用した方法（CCM）、SNaPshot法、MassArray法、Pyrosequencing法、SNP-IT法、BeadArray法、Scorpion法、MADI-TOF/MS法等が挙げられる。また、各一塩基多型の遺伝子型をオリゴDNAタグへ変換し、DNAチップとのハイブリダイゼーションにより解析を行うDigiTag2法を用いることもできる。DigiTag2法は、Srilohasin P et al. J. Clin. Microbiol. 2014, 52(6): 1962-8、Nishida N et al., Analytical Biochemistry 346(2):281-288、Nishida et al., Analytical Biochemistry 364(1):78-85等の記載に従って行うことができる。 The analysis of single nucleotide polymorphism can be performed by a conventional gene polymorphism analysis method. For example, an analysis method by sequence analysis in which the sequence is directly determined by a known method such as the dideoxy method or Maxam-Gilbert method, a probe specific for gene polymorphism or a hybridization using a microarray (DNA chip) on which the probe is immobilized Methods, various methods using primers specific for gene polymorphism, etc., and more specifically, primer extension method (TaqMan (registered trademark) method), PCR-SSCP method, single-strand conformation polymorphism analysis (SSCP; single strand conformation polymorphism), Invader method, single nucleotide primer method, PCR method, NASBA method, LCR method, SDA method, LAMP method, method using restriction fragment length polymorphism (RFLP), denaturing gradient gel electrophoresis Method (DGGE), Method using chemical cleavage of mismatch site (CCM), SNaPshot method, MassArray method, Pyrosequencing method, SNP-IT method, BeadArray method, Scorpion method, MADI- A TOF / MS method etc. are mentioned. Alternatively, DigiTag 2 method may be used in which each single nucleotide polymorphism genotype is converted to an oligo DNA tag and analysis is performed by hybridization with a DNA chip. The DigiTag 2 method is described in Srilohasin P et al. J. Clin. Microbiol. 2014, 52 (6): 1962-8, Nishida N et al., Analytical Biochemistry 346 (2): 281-288, Nishida et al., Analytical Biochemistry. 364 (1): 78-85 and the like.
　シークエンス解析による解析は、通常の方法により行うことができる。具体的には、一塩基多型部位の５’側の数十塩基の位置に設定したプライマーを使用してシークエンス反応を行い、その解析結果から、一塩基多型部位の塩基を決定することができる。 The analysis by sequence analysis can be performed by a conventional method. Specifically, a sequence reaction is performed using a primer set at the position of several tens of bases on the 5 'side of the single nucleotide polymorphism site, and the base of the single nucleotide polymorphism site can be determined from the analysis result it can.
　プライマーを用いる方法は、一塩基多型部位を含む遺伝子配列の一部に対応するプライマーを用いて、被験体から単離した核酸サンプルを増幅させて行う。すなわち、例えば、一方のアリルに完全又はほぼ完全に相補的なプライマーと他方のアリルにのみ完全又はほぼ完全に相補的なプライマーを用い、各プライマーを用いた場合に被験体から単離した核酸サンプルが増幅されるか否かにより一塩基多型のアリルを同定することができる。また、一方のアリルに対応するプライマーのみを用いてもよい。 The method of using a primer is carried out by amplifying a nucleic acid sample isolated from a subject using a primer corresponding to a part of a gene sequence containing a single nucleotide polymorphism site. That is, for example, a nucleic acid sample isolated from a subject when each primer is used, using a primer completely or almost completely complementary to one allele and a primer completely or almost completely complementary to the other allele. The allele of single nucleotide polymorphism can be identified depending on whether or not is amplified. Alternatively, only a primer corresponding to one of the alleles may be used.
　プローブを用いる方法は、一塩基多型部位を含む遺伝子配列の一部に対応するオリゴヌクレオチド又はその相補的配列、あるいはストリンジェント条件下でそれらの配列にハイブリダイズし得る配列からなるオリゴヌクレオチドからなるプローブを用いて、被験体から単離した核酸サンプル、又はそれをPCR等の公知の方法により増幅した核酸サンプルとのハイブリダイゼーションを行うことにより分析することができる。すなわち、一方のアリルに完全又はほぼ完全（例えば、対象とする一塩基多型部位に連続した塩基配列部分が70％以上の配列同一性、好ましくは80％以上の配列同一性、より好ましくは90％以上の配列同一性、特に好ましくは95％以上の配列同一性を有することをいう）に相補的なプローブと他方のアリルにのみ完全又はほぼ完全に相補的なプローブを用い、各プローブを用いた場合に被験体から単離した核酸サンプル又はそれを増幅した核酸サンプルとハイブリダイズするか否かにより一塩基多型のアリルを同定することができる。また、一方のアリルに対応したプローブのみを用いてもよい。ハイブリダイゼーションの条件は、一塩基多型を区別するのに十分な条件であればよく、例えば一塩基多型部位が特定のアリルの場合にはハイブリダイズするが、他のアリルの場合にはハイブリダイズしないような条件、例えばストリンジェントな条件であり、このような条件は当業者ならば適宜設定することができる。　プローブは、一端を基板に固定してDNAチップ（マイクロアレイ）として使用してもよい。この場合、DNAチップには、１つの遺伝子多型部位に対応するプローブのみが固定されていても、複数の一塩基多型部位に対応するプローブが固定されていてもよい。 The method using a probe consists of an oligonucleotide corresponding to a part of the gene sequence containing a single nucleotide polymorphism site or a complementary sequence thereof, or an oligonucleotide consisting of a sequence capable of hybridizing to these sequences under stringent conditions. The probe can be used for analysis by hybridization of a nucleic acid sample isolated from a subject, or a nucleic acid sample amplified by a known method such as PCR. That is, complete or almost complete (for example, 70% or more sequence identity, preferably 80% or more sequence identity, of the base sequence portion continuous to the target single nucleotide polymorphism site) to one allyl. Each probe using a probe complementary to% or more of sequence identity, particularly preferably having a sequence identity of 95% or more, and a probe completely or almost completely complementary only to the other allele The allele of single nucleotide polymorphism can be identified depending on whether it hybridizes with the nucleic acid sample isolated from the subject or the nucleic acid sample amplified from the subject when it has been. Alternatively, only probes corresponding to one of the alleles may be used. The hybridization conditions may be any conditions sufficient to distinguish single nucleotide polymorphisms, for example, hybridization occurs when the single nucleotide polymorphism site is a specific allele, while hybridization occurs when the other alleles Conditions that do not cause soybeans, such as stringent conditions, can be set as appropriate by those skilled in the art. The probe may be used as a DNA chip (microarray) by fixing one end to a substrate. In this case, even if only a probe corresponding to one gene polymorphism site is immobilized, a probe corresponding to a plurality of single nucleotide polymorphism sites may be immobilized on the DNA chip.
　一塩基多型を検出するためのプローブやプライマーは、一塩基多型の配列情報に基づいて適宜設計することができる。 Probes and primers for detecting single nucleotide polymorphisms can be appropriately designed based on the sequence information of single nucleotide polymorphisms.
　プローブは、一塩基多型部位を含む塩基配列又は該塩基配列に相補的な塩基配列或いはストリンジェント条件下でそれらの配列にハイブリダイズし得る配列からなるヌクレオチド断片（好ましくは、DNA断片）からなり、塩基の数は5～50、好ましくは10～30、さらに好ましくは10～25である。 The probe consists of a nucleotide sequence (preferably, a DNA fragment) consisting of a nucleotide sequence containing a single nucleotide polymorphism site or a nucleotide sequence complementary to the nucleotide sequence or a sequence capable of hybridizing to the sequences under stringent conditions. The number of bases is 5 to 50, preferably 10 to 30, and more preferably 10 to 25.
　プライマーは、一塩基多型部位のアリルを同定できるプライマーであり、例えば、一塩基多型部位を含む配列を有する領域を増幅することのできる配列である。これらのプライマーは、一塩基多型部位を含む配列を含んでいてもよく、また一塩基多型部位を含む領域（好ましくは４０～１０００塩基の長さの領域）の3’側と5’側の両端に設定されたフォワードプライマーとリバースプライマーのプライマー対であってもよい。プライマーは、一塩基多型部位を含む塩基配列又は該塩基配列に相補的な塩基配列或いはストリンジェント条件下でそれらの配列にハイブリダイズし得る配列からなるヌクレオチド断片（好ましくは、DNA断片）からなり、塩基の数は5～50、好ましくは10～30、さらに好ましくは15～25である。 The primer is a primer capable of identifying an allele at a single nucleotide polymorphism site, and is, for example, a sequence capable of amplifying a region having a sequence containing a single nucleotide polymorphism site. These primers may contain a sequence containing a single nucleotide polymorphism site, and may be 3 'and 5' to a region containing a single nucleotide polymorphism site (preferably a region of 40 to 1000 bases in length). There may be a primer pair of forward primer and reverse primer set at both ends of. The primer is composed of a nucleotide sequence (preferably a DNA fragment) consisting of a nucleotide sequence containing a single nucleotide polymorphism site or a nucleotide sequence complementary to the nucleotide sequence or a sequence capable of hybridizing to these sequences under stringent conditions. And the number of bases is 5 to 50, preferably 10 to 30, and more preferably 15 to 25.
　また、プローブ又はプライマーは一塩基多型部位を含む連続した塩基配列において、数個、好ましくは1～5個、さらに好ましくは１個又は２個、特に好ましくは１個のミスマッチを含んでいてもよい。 Also, the probe or primer may contain several, preferably 1 to 5, more preferably 1 or 2, particularly preferably 1 mismatch in the continuous base sequence including the single nucleotide polymorphism site. Good.
　本発明は、上記の一塩基多型を分析するために用いるプローブ及び一塩基多型を分析するために一塩基多型部位を含むDNA断片の増幅に用いるプライマー（好ましくは、少なくとも一対のプライマーセット）を包含する。また、プローブを固定化したDNAチップをも包含する。さらに、プローブ、DNAチップ、プライマーを含む上記の一塩基多型部位を解析するためのキットも包含する。 The present invention relates to a probe used to analyze the above single nucleotide polymorphism and a primer used to amplify a DNA fragment containing a single nucleotide polymorphism site to analyze the single nucleotide polymorphism (preferably, at least a pair of primer sets) ). It also includes a DNA chip on which a probe is immobilized. Furthermore, a kit for analyzing the above-mentioned single nucleotide polymorphism site containing a probe, a DNA chip, and a primer is also included.
　該キットは、他に一塩基多型の解析に使用される制限酵素、ポリメラーゼ、ヌクレオシド三リン酸、核酸標識分子、緩衝液、該キットの取扱説明書等を含んでいてもよい。 The kit may additionally contain a restriction enzyme, a polymerase, nucleoside triphosphate, a nucleic acid labeling molecule, a buffer, an instruction manual for the kit, etc. which are used for analysis of single nucleotide polymorphisms.
　一塩基多型部位の解析に用いるプローブ又はプライマーとして以下のものを挙げることができる。 The following can be mentioned as a probe or a primer used for analysis of a single nucleotide polymorphism site.
北京株感染被験体における結核症発症のリスクを判定するためのプライマー
(p1)　配列番号１の塩基配列における26番目の塩基（rs9348878の多型部位の塩基）を含む領域を増幅することができるプライマー
(p2)　配列番号２の塩基配列における26番目の塩基（rs2070600の多型部位の塩基）を含む領域を増幅することができるプライマー
(p3)　配列番号３の塩基配列における26番目の塩基（rs401864の多型部位の塩基）を含む領域を増幅することができるプライマー
(p4)　配列番号４の塩基配列における26番目の塩基（rs673119の多型部位の塩基）を含む領域を増幅することができるプライマー
(p5)　配列番号５の塩基配列における26番目の塩基（rs1321267の多型部位の塩基）を含む領域を増幅することができるプライマー
(p6)　配列番号６の塩基配列における26番目の塩基（rs2076625の多型部位の塩基）を含む領域を増幅することができるプライマー
(p7)　配列番号７の塩基配列における26番目の塩基（rs7142055の多型部位の塩基）を含む領域を増幅することができるプライマー
(p8)　配列番号８の塩基配列における26番目の塩基（rs1157619の多型部位の塩基）を含む領域を増幅することができるプライマー
(p9)　配列番号９の塩基配列における26番目の塩基（rs4924568の多型部位の塩基）を含む領域を増幅することができるプライマー
(p10)　配列番号10の塩基配列における26番目の塩基（rs1899820の多型部位の塩基）を含む領域を増幅することができるプライマー
(p11)　配列番号11の塩基配列における26番目の塩基（rs2695163の多型部位の塩基）を含む領域を増幅することができるプライマー
(p12)　配列番号12の塩基配列における26番目の塩基（rs1197772の多型部位の塩基）を含む領域を増幅することができるプライマー
(p13)　配列番号13の塩基配列における26番目の塩基（rs1081022の多型部位の塩基）を含む領域を増幅することができるプライマー
(p14)　配列番号14の塩基配列における26番目の塩基（rs1648835の多型部位の塩基）を含む領域を増幅することができるプライマー Primers for determining the risk of developing tuberculosis in a Beijing strain-infected subject
(p1) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs9348878) in the base sequence of SEQ ID NO: 1
(p2) A primer capable of amplifying a region containing the 26th base (a base at the polymorphic site of rs2070600) in the nucleotide sequence of SEQ ID NO: 2
(p3) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs401864) in the nucleotide sequence of SEQ ID NO: 3
(p4) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs673119) in the nucleotide sequence of SEQ ID NO: 4
(p5) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1321267) in the nucleotide sequence of SEQ ID NO: 5
(p6) A primer capable of amplifying a region including the 26th base (a base of polymorphic site of rs2076625) in the nucleotide sequence of SEQ ID NO: 6
(p7) A primer capable of amplifying a region including the 26th base (base of polymorphic site of rs7142055) in the nucleotide sequence of SEQ ID NO: 7
(p8) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1157619) in the nucleotide sequence of SEQ ID NO: 8
(p9) A primer capable of amplifying a region containing the 26th base (a base at the polymorphic site of rs4924568) in the nucleotide sequence of SEQ ID NO: 9
(p10) A primer capable of amplifying a region containing the 26th base (a base at the polymorphic site of rs1899820) in the nucleotide sequence of SEQ ID NO: 10
(p11) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs2695163) in the base sequence of SEQ ID NO: 11
(p12) A primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1197772) in the nucleotide sequence of SEQ ID NO: 12
(p13) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1081022) in the nucleotide sequence of SEQ ID NO: 13
(p14) A primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs 1648835) in the nucleotide sequence of SEQ ID NO: 14
非北京株感染被験体における結核症発症のリスクを判定するためのプライマー
(p15)　配列番号15の塩基配列における26番目の塩基（rs12144738の多型部位の塩基）を含む領域を増幅することができるプライマー
(p16)　配列番号16の塩基配列における26番目の塩基（rs1494320の多型部位の塩基）を含む領域を増幅することができるプライマー
(p17)　配列番号17の塩基配列における26番目の塩基（rs1712674の多型部位の塩基）を含む領域を増幅することができるプライマー
(p18)　配列番号18の塩基配列における26番目の塩基（rs1418425の多型部位の塩基）を含む領域を増幅することができるプライマー
(p19)　配列番号19の塩基配列における26番目の塩基（rs4688637の多型部位の塩基）を含む領域を増幅することができるプライマー
(p20)　配列番号20の塩基配列における26番目の塩基（rs12374531の多型部位の塩基）を含む領域を増幅することができるプライマー
(p21)　配列番号21の塩基配列における26番目の塩基（rs11784415の多型部位の塩基）を含む領域を増幅することができるプライマー
(p22)　配列番号22の塩基配列における26番目の塩基（rs2182093の多型部位の塩基）を含む領域を増幅することができるプライマー
(p23)　配列番号23の塩基配列における26番目の塩基（rs10798の多型部位の塩基）を含む領域を増幅することができるプライマー
(p24)　配列番号24の塩基配列における26番目の塩基（rs4267316の多型部位の塩基）を含む領域を増幅することができるプライマー
(p25)　配列番号25の塩基配列における26番目の塩基（rs6071980の多型部位の塩基）を含む領域を増幅することができるプライマー
(p26)　配列番号26の塩基配列における26番目の塩基（rs743057の多型部位の塩基）を含む領域を増幅することができるプライマー Primers for determining the risk of developing tuberculosis in non-Beijing strains infected subjects
(p15) A primer capable of amplifying a region including the 26th base (base of polymorphic site of rs12144738) in the nucleotide sequence of SEQ ID NO: 15
(p16) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16
(p17) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1712674) in the nucleotide sequence of SEQ ID NO: 17
(p18) A primer capable of amplifying a region containing the 26th base (a base at the polymorphic site of rs1418425) in the nucleotide sequence of SEQ ID NO: 18
(p19) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs4688637) in the nucleotide sequence of SEQ ID NO: 19
(p20) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs12374531) in the nucleotide sequence of SEQ ID NO: 20
(p21) A primer capable of amplifying a region including the 26th base (base of polymorphic site of rs11784415) in the nucleotide sequence of SEQ ID NO: 21
(p22) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs2182093) in the nucleotide sequence of SEQ ID NO: 22
(p23) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10798) in the base sequence of SEQ ID NO: 23
(p24) A primer capable of amplifying a region containing the 26th base in the nucleotide sequence of SEQ ID NO: 24 (the base of polymorphic site of rs 4267 316)
(p25) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs6071980) in the nucleotide sequence of SEQ ID NO: 25
(p26) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs743057) in the nucleotide sequence of SEQ ID NO: 26
EAI株感染被験体における結核症発症のリスクを判定するためのプライマー
(p27)　配列番号27の塩基配列における26番目の塩基（rs1178938の多型部位の塩基）を含む領域を増幅することができるプライマー
(p28)　配列番号28の塩基配列における26番目の塩基（rs800065の多型部位の塩基）を含む領域を増幅することができるプライマー
(p29)　配列番号29の塩基配列における26番目の塩基（rs1372667の多型部位の塩基）を含む領域を増幅することができるプライマー
(p30)　配列番号30の塩基配列における26番目の塩基（rs13174549の多型部位の塩基）を含む領域を増幅することができるプライマー
(p31)　配列番号31の塩基配列における26番目の塩基（rs7087410の多型部位の塩基）を含む領域を増幅することができるプライマー
(p32)　配列番号32の塩基配列における26番目の塩基（rs10898382の多型部位の塩基）を含む領域を増幅することができるプライマー
(p33)　配列番号33の塩基配列における26番目の塩基（rs951729の多型部位の塩基）を含む領域を増幅することができるプライマー
(p34)　配列番号34の塩基配列における26番目の塩基（rs1658693の多型部位の塩基）を含む領域を増幅することができるプライマー Primers for determining the risk of developing tuberculosis in an EAI strain infected subject
(p27) A primer capable of amplifying a region including the 26th base (base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27
(p28) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs8000065) in the nucleotide sequence of SEQ ID NO: 28
(p29) A primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1372667) in the nucleotide sequence of SEQ ID NO: 29
(p30) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs13174549) in the nucleotide sequence of SEQ ID NO: 30
(p31) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs7087410) in the base sequence of SEQ ID NO: 31
(p32) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10898382) in the nucleotide sequence of SEQ ID NO: 32
(p33) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs951729) in the base sequence of SEQ ID NO: 33
(p34) A primer capable of amplifying a region containing the 26th base (a base at polymorphic site of rs1658693) in the base sequence of SEQ ID NO: 34
非EAI株感染被験体における結核症発症のリスクを判定するためのプライマー
(p35)　配列番号35の塩基配列における26番目の塩基（rs1820920の多型部位の塩基）を含む領域を増幅することができるプライマー
(p36)　配列番号36の塩基配列における26番目の塩基（rs11737270の多型部位の塩基）を含む領域を増幅することができるプライマー
(p37)　配列番号37の塩基配列における26番目の塩基（rs10832678の多型部位の塩基）を含む領域を増幅することができるプライマー
(p38)　配列番号38の塩基配列における26番目の塩基（rs10507084の多型部位の塩基）を含む領域を増幅することができるプライマー
(p39)　配列番号39の塩基配列における26番目の塩基（rs1440548の多型部位の塩基）を含む領域を増幅することができるプライマー Primers for determining the risk of developing tuberculosis in non-EAI strain infected subjects
(p35) A primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs1820920) in the nucleotide sequence of SEQ ID NO: 35
(p36) A primer capable of amplifying a region including the 26th base (base of polymorphic site of rs11737270) in the nucleotide sequence of SEQ ID NO: 36
(p37) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10832678) in the base sequence of SEQ ID NO: 37
(p38) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10507084) in the nucleotide sequence of SEQ ID NO: 38
(p39) A primer capable of amplifying a region containing the 26th base (a base at polymorphic site of rs 1440548) in the nucleotide sequence of SEQ ID NO: 39
北京株感染被験体における結核症発症のリスクを判定するためのプローブ
(q1)　配列番号１の塩基配列における26番目の塩基（rs9348878の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q2)　配列番号２の塩基配列における26番目の塩基（rs2070600の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q3)　配列番号３の塩基配列における26番目の塩基（rs401864の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q4)　配列番号４の塩基配列における26番目の塩基（rs673119の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q5)　配列番号５の塩基配列における26番目の塩基（rs1321267の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q6)　配列番号６の塩基配列における26番目の塩基（rs2076625の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q7)　配列番号７の塩基配列における26番目の塩基（rs7142055の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q8)　配列番号８の塩基配列における26番目の塩基（rs1157619の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q9)　配列番号９の塩基配列における26番目の塩基（rs4924568の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q10)　配列番号10の塩基配列における26番目の塩基（rs1899820の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q11)　配列番号11の塩基配列における26番目の塩基（rs2695163の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q12)　配列番号12の塩基配列における26番目の塩基（rs1197772の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q13)　配列番号13の塩基配列における26番目の塩基（rs1081022の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q14)　配列番号14の塩基配列における26番目の塩基（rs1648835の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ Probes to determine the risk of developing tuberculosis in a Beijing strain-infected subject
(q1) A probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs9348878) in the base sequence of SEQ ID NO: 1
(q2) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs2070600) in the base sequence of SEQ ID NO: 2
(q3) A probe capable of hybridizing to a region containing the 26th base (base of polymorphic site of rs401864) in the base sequence of SEQ ID NO: 3
(q4) A probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs673119) in the base sequence of SEQ ID NO: 4
(q5) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs1321267) in the base sequence of SEQ ID NO: 5
(q6) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs 2076625) in the base sequence of SEQ ID NO: 6
(q7) A probe capable of hybridizing to a region containing the 26th base (base of polymorphic site of rs7142055) in the base sequence of SEQ ID NO: 7
(q8) A probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1157619) in the nucleotide sequence of SEQ ID NO: 8
(q9) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs4924568) in the base sequence of SEQ ID NO: 9
(q10) A probe capable of hybridizing to a region including the 26th base (a base at the polymorphic site of rs1899820) in the base sequence of SEQ ID NO: 10
(q11) A probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs2695163) in the base sequence of SEQ ID NO: 11
(q12) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1197772) in the base sequence of SEQ ID NO: 12
(q13) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1081022) in the base sequence of SEQ ID NO: 13
(q14) A probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs 1648835) in the base sequence of SEQ ID NO: 14
非北京株感染被験体における結核症発症のリスクを判定するためのプローブ
(q15)　配列番号15の塩基配列における26番目の塩基（rs12144738の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q16)　配列番号16の塩基配列における26番目の塩基（rs1494320の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q17)　配列番号17の塩基配列における26番目の塩基（rs1712674の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q18)　配列番号18の塩基配列における26番目の塩基（rs1418425の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q19)　配列番号19の塩基配列における26番目の塩基（rs4688637の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q20)　配列番号20の塩基配列における26番目の塩基（rs12374531の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q21)　配列番号21の塩基配列における26番目の塩基（rs11784415の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q22)　配列番号22の塩基配列における26番目の塩基（rs2182093の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q23)　配列番号23の塩基配列における26番目の塩基（rs10798の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q24)　配列番号24の塩基配列における26番目の塩基（rs4267316の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q25)　配列番号25の塩基配列における26番目の塩基（rs6071980の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q26)　配列番号26の塩基配列における26番目の塩基（rs743057の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ Probes for determining the risk of developing tuberculosis in non-Beijing strains infected subjects
(q15) A probe capable of hybridizing to a region including the 26th base (a base at the polymorphic site of rs12144738) in the nucleotide sequence of SEQ ID NO: 15
(q16) a probe capable of hybridizing to a region containing the 26th base (the base at the polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16
(q17) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs1712674) in the base sequence of SEQ ID NO: 17
(q18) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1418425) in the base sequence of SEQ ID NO: 18
(q19) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs4688637) in the nucleotide sequence of SEQ ID NO: 19
(q20) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs12374531) in the base sequence of SEQ ID NO: 20
(q21) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs11784415) in the base sequence of SEQ ID NO: 21
(q22) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs2182093) in the base sequence of SEQ ID NO: 22
(q23) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10798) in the base sequence of SEQ ID NO: 23
(q24) A probe capable of hybridizing to a region including the 26th base (a base at the polymorphic site of rs 4267 316) in the nucleotide sequence of SEQ ID NO: 24
(q25) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs6071980) in the base sequence of SEQ ID NO: 25
(q26) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs743057) in the base sequence of SEQ ID NO: 26
EAI株感染被験体における結核症発症のリスクを判定するためのプローブ
(q27)　配列番号27の塩基配列における26番目の塩基（rs1178938の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q28)　配列番号28の塩基配列における26番目の塩基（rs800065の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q29)　配列番号29の塩基配列における26番目の塩基（rs1372667の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q30)　配列番号30の塩基配列における26番目の塩基（rs13174549の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q31)　配列番号31の塩基配列における26番目の塩基（rs7087410の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q32)　配列番号32の塩基配列における26番目の塩基（rs10898382の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q33)　配列番号33の塩基配列における26番目の塩基（rs951729の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q34)　配列番号34の塩基配列における26番目の塩基（rs1658693の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ Probe for determining the risk of developing tuberculosis in an EAI strain infected subject
(q27) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27
(q28) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs8000065) in the base sequence of SEQ ID NO: 28
(q29) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1372667) in the base sequence of SEQ ID NO: 29
(q30) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs13174549) in the base sequence of SEQ ID NO: 30
(q31) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs7087410) in the nucleotide sequence of SEQ ID NO: 31
(q32) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10898382) in the nucleotide sequence of SEQ ID NO: 32
(q33) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs951729) in the base sequence of SEQ ID NO: 33
(q34) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1658693) in the base sequence of SEQ ID NO: 34
非EAI株感染被験体における結核症発症のリスクを判定するためのプローブ
(q35)　配列番号35の塩基配列における26番目の塩基（rs1820920の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q36)　配列番号36の塩基配列における26番目の塩基（rs11737270の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q37)　配列番号37の塩基配列における26番目の塩基（rs10832678の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q38)　配列番号38の塩基配列における26番目の塩基（rs10507084の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ
(q39)　配列番号39の塩基配列における26番目の塩基（rs1440548の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ Probes for determining the risk of developing tuberculosis in non-EAI strain infected subjects
(q35) a probe capable of hybridizing to a region including the 26th base (base of polymorphic site of rs1820920) in the nucleotide sequence of SEQ ID NO: 35
(q36) a probe capable of hybridizing to a region containing the 26th base (the base at the polymorphic site of rs11737270) in the nucleotide sequence of SEQ ID NO: 36
(q37) a probe capable of hybridizing to a region containing the 26th base (the base at the polymorphic site of rs10832678) in the nucleotide sequence of SEQ ID NO: 37
(q38) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10507084) in the base sequence of SEQ ID NO: 38
(q39) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs 1440548) in the base sequence of SEQ ID NO: 39
　被験体が感染している結核菌が北京株であるときに、上記の(p1)～(p14)の少なくとも１つ、好ましくは２、３、４、５、６、７、８、９、10、11、12、13又は14個のプライマーを用い、被験体が感染している結核菌が非北京株であるときに、上記の(p15)～(p26)の少なくとも１つ、好ましくは２、３、４、５、６、７、８、９、10、11又は12個のプライマーを用い、被験体が感染している結核菌がEAI株であるときに、上記の(p27)～(p34)の少なくとも１つ、好ましくは２、３、４、５、６、７又は８個のプライマーを用い、被験体が感染している結核菌が非EAI株であるときに、上記の(p35)～(p39)の少なくとも１つ、好ましくは２、３、４又は５個のプライマーを用い、一塩基多型を同定すればよい。プライマーは好ましくはフォワードプライマーとリバースプライマーのプライマー対として用いる。 When the Mycobacterium tuberculosis with which the subject is infected is a Beijing strain, at least one of (p1) to (p14) above, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 primers, and at least one of (p15) to (p26) above, preferably 2, when the M. tuberculosis strain with which the subject is infected is a non-Beijing strain, When 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 primers are used and the tubercle bacillus infecting the subject is the EAI strain, the above (p27) to (p34) Using at least one, preferably 2, 3, 4, 5, 6, 7 or 8 primers of the above (p35) when the tubercle bacillus infecting the subject is a non-EAI strain. The single nucleotide polymorphism may be identified using at least one, preferably 2, 3, 4 or 5 primers of to (p39). The primer is preferably used as a primer pair of forward and reverse primers.
　また、被験体が感染している結核菌が北京株であるときに、上記の(q1)～(q14)の少なくとも１つ、好ましくは２、３、４、５、６、７、８、９、10、11、12、13又は14個のプローブを用い、被験体が感染している結核菌が非北京株であるときに、上記の(q15)～(q26)の少なくとも１つ、好ましくは２、３、４、５、６、７、８、９、10、11又は12個のプローブを用い、被験体が感染している結核菌がEAI株であるときに、上記の(q27)～(q34)の少なくとも１つ、好ましくは２、３、４、５、６、７又は８個のプローブを用い、被験体が感染している結核菌が非EAI株であるときに、上記の(q35)～(q39)の少なくとも１つ、好ましくは２、３、４又は５個のプローブを用い、一塩基多型を同定すればよい。 In addition, when the M. tuberculosis organism with which the subject is infected is a Beijing strain, at least one of the above (q1) to (q14), preferably 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, or 14 probes, and at least one of (q15) to (q26) described above is used, preferably when the M. tuberculosis strain with which the subject is infected is a non-Beijing strain. When 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 probes are used and the tubercle bacillus infecting the subject is the EAI strain, the above (q27) Using at least one, preferably 2, 3, 4, 5, 6, 7 or 8 probes of (q34), when the M. tuberculosis strain with which the subject is infected is a non-EAI strain, A single nucleotide polymorphism may be identified using at least one, preferably 2, 3, 4 or 5 probes of q35) to (q39).
　本発明は、上記のプライマー又はプローブを含む、結核症発症のリスクを判定するための試薬又はキットを包含する。 The present invention includes a reagent or kit for determining the risk of developing tuberculosis, which comprises the above-described primer or probe.
　上記の一塩基多型部位の近傍に位置する遺伝子の発現は、各遺伝子のmRNAを測定しても、発現したタンパク質を測定してもよい。好ましくは、mRNAを測定する。mRNA又はタンパク質は、組織や細胞から抽出したものを測定すればよい。 The expression of the gene located in the vicinity of the single nucleotide polymorphism site may be determined by measuring the mRNA of each gene or measuring the expressed protein. Preferably, mRNA is measured. The mRNA or protein may be measured from tissue or cells.
　組織や細胞中のmRNAの測定は、例えば、組織又は細胞からRNAを抽出し、cDNAに逆転写し、該cDNAを測定すればよい。cDNAの測定は、各遺伝子の配列情報を利用して、各遺伝子に相補的にハイブリダイズするプローブ又はプライマーを用いて行うことができる。プローブ又はプライマーを用いた測定は、上記の一塩基多型を検出する方法に準じて行うことができる。 For measurement of mRNA in a tissue or cell, for example, RNA may be extracted from the tissue or cell, reverse transcribed to cDNA, and the cDNA may be measured. The measurement of cDNA can be performed using a probe or a primer that hybridizes complementarily to each gene using sequence information of each gene. The measurement using a probe or a primer can be performed according to the method of detecting the single nucleotide polymorphism described above.
　タンパク質の測定は、組織や細胞からタンパク質を抽出し、該タンパク質に対するモノクローナル抗体等の抗体を用いて抗原抗体反応を利用したイムノアッセイにより行うことができる。また、採取した組織又は細胞に対して前記抗体を利用した免疫組織化学、免疫細胞化学による染色により、測定することもできる。 The measurement of the protein can be performed by extracting the protein from tissues or cells, and using an antibody such as a monoclonal antibody against the protein by an immunoassay using an antigen-antibody reaction. In addition, it can also be measured by immunohistochemistry, immunocytochemistry staining using the above-described antibody, on collected tissues or cells.
　本発明の方法により、結核症を発症するリスクが高いと判定された場合は、被験体に（１）リファンピシン、（２）イソニアジド、（３）ストレプトマイシン、（４）エタンブトール、（５）ピラジナミド等の抗生物質を適宜組合せて数か月にわたって投与すればよい。例えば、（１）と（２）と（４）若しくは（３）と（５）を約２カ月投与し、その後（１）と（２）を約４か月投与すればよい。 When it is determined that the risk of developing tuberculosis is high according to the method of the present invention, the subject is given (1) rifampicin, (2) isoniazid, (3) streptomycin, (4) ethambutol, (5) pyrazinamide, etc. Antibiotics may be combined as appropriate and administered over several months. For example, (1) and (2) and (4) or (3) and (5) may be administered for about 2 months, and thereafter (1) and (2) may be administered for about 4 months.
　本発明を以下の実施例によって具体的に説明するが、本発明はこれらの実施例によって限定されるものではない。 The present invention is specifically described by the following examples, but the present invention is not limited by these examples.
　本発明はタイ王国内で収集された結核症発症者及び健常者を対象とした解析結果に基づく。結核症の診断は患者の喀痰からの結核菌の培養判定に基づき、陽性であったものを結核症発症者と判定した。HIVウイルスに共感染していた患者は除外されている。健常者は結核の病歴がない者である。患者の血液及び感染結核菌よりDNA抽出を行った。 The present invention is based on the analysis results for tuberculosis and healthy people collected in Thailand. The diagnosis of tuberculosis was based on the culture determination of M. tuberculosis from the sputum of the patient, and those that were positive were determined to be those who developed tuberculosis. Patients who were coinfected with the HIV virus are excluded. Healthy persons are those who have no history of tuberculosis. DNA was extracted from the patient's blood and infected M. tuberculosis.
　ヒトゲノムのSNP情報は、Illumina社製造のSNPタイピング用マイクロアレイであるIllumina Human610-Quad v1.0又はIllumina HumanOmniExpressExome-8 v1.2によって得た。2つのアレイで共通する338,476 SNPs由来の遺伝子型情報が本発明の実施過程で解析対象となっている。検体データの品質管理としてはゲノム全域のSNPにおける遺伝子型の決定率が98％以上の検体を採用した。SNPデータの品質管理としては(1)全検体中95％以上の検体で遺伝子型が決定され、(2)全検体中でマイナーアリルの頻度が５％以上あり、かつ(3)健常者検体中のハーディワインベルグ平衡検定においてP値が0.001以上と大きく理論値と異ならないという３条件を全て満たしたSNPを採用した。最終的に、266,604個の常染色体上のSNPsが関連解析に用いられた。 The SNP information of the human genome was obtained by Illumina Human610-Quad v1.0 or Illumina Human OmniExpressExome-8 v1.2, which are microarrays for SNP typing manufactured by Illumina. Genotype information derived from 338, 476 SNPs common to the two arrays is to be analyzed in the process of the present invention. For quality control of sample data, a sample with a genotype determination rate of 98% or more for SNPs in the entire genome was adopted. As quality control of SNP data, (1) the genotype is determined in 95% or more of all samples, (2) the frequency of minor allele is 5% or more in all samples, and (3) in healthy subject samples In the Hardy-Weinberg equilibrium test of S., a SNP satisfying all three conditions that the P value was not significantly different from the theoretical value of 0.001 or more was adopted. Finally, 266,604 autosomal SNPs were used for association analysis.
　すべての検体は前記のデータ品質管理をクリアしたSNPsを用いたidentity by descent (IBD) 検定を行い、重複検体もしくは第一度近親者検体を含まないことを確認している。また、国際Hapmapプロジェクトの公開データ[GSE17205 (CEU), GSE17206 (CHB+JPT)及びGSE17207 (YRI)]をコントロールとした主成分分析により、関連解析に用いる全てのタイ人検体がアジア人集団に含まれることを確認している。さらに、タイ人集団は遺伝的背景に多様性があることから、ヒトゲノム全域のSNPs情報を用いた主成分分析を実施し、関連解析を実施する前に、収集したタイ人患者から健常者群と同様の遺伝的背景を持つ患者群を抽出した。抽出の結果、解析対象とした全1784検体中で遺伝的背景が近い1,457検体が選択され、結核患者686検体と健常者771検体が含まれた。全ての結核患者検体から感染結核菌のゲノムが抽出されている。 All samples were tested for identity by descent (IBD) using SNPs that cleared the data quality control described above, and it was confirmed that they did not contain duplicate samples or first-degree relative samples. In addition, all Thai specimens used for association analysis are included in the Asian population by principal component analysis using the international Hapmap project public data [GSE17205 (CEU), GSE17206 (CHB + JPT) and GSE17207 (YRI)] as controls. Have confirmed that Furthermore, because the Thai population is diverse in genetic background, principal component analysis using SNPs information on the entire human genome was performed, and Thai patients collected from the Thai population and healthy people were A group of patients with similar genetic background was extracted. As a result of extraction, 1,457 samples having a close genetic background were selected among all 1784 samples to be analyzed, and 686 samples of tuberculosis patients and 771 samples of healthy persons were included. The genome of infected M. tuberculosis has been extracted from all M. tuberculosis patient samples.
　同時に、抽出した感染結核菌のゲノムを用いて、結核菌の遺伝系統の判別を行った。判定には抽出したゲノムDNAを鋳型とするPCR法に基づくLSP（large sequence polymorphism）法を用いて行った。具体的には、EAI株、北京株、CAS株、Euro-American株及びその他という５つの遺伝系統に分類するため、マーカーとなる結核菌ゲノム領域として、TbD1, RD105, RD239, 7bp deletion at pks15/1 及び RD750という5つのゲノム領域を組み合わせた。各ゲノム領域に対する特異的なプライマーセットにより対象領域を増幅することで、その増幅産物のサイズにより対象領域の欠失の有無を判定し、その結果から遺伝系統を判定した。EAI株はRD239(-)かつTbD1(+)であり、北京株はRD105(-)かつTbD1(-)であり、CAS株はRD750(-)かつTbD1(-)であり、Euro-American株はTbD1(-)かつ7bp deletion at pks 15/1である。その他の株はTbD1(-)かつその他４領域全て(+)であった。スポリゴタイピングによる分類も行ったが、LSP法による分類結果と一致するものであった。今回用いた全ての検体は単一の遺伝系統による感染であった。本発明では、北京（Beijing)株は感染者が多いため、北京株以外の株をまとめて非北京株と呼び、非北京(Non-Beijing)株にはEAI株、CAS株及びEuro-American株が含まれる。同様に、EAI株は感染者が多いため、EAI株以外の株をまとめて非EAI株と呼び、非EAI株には北京株、CAS株及びEuro-American株が含まれる。 At the same time, the genetic strain of M. tuberculosis was identified using the extracted M. tuberculosis genome. The determination was carried out using a large sequence polymorphism (LSP) method based on PCR using the extracted genomic DNA as a template. Specifically, TbD1, RD105, RD239, 7 bp deletion at pks15 / as the M. tuberculosis genome region serving as a marker for classification into five genetic lines: EAI strain, Beijing strain, CAS strain, Euro-American strain and others. 1 and 5 genome regions of RD750 were combined. By amplifying the target region with a specific primer set for each genomic region, the presence or absence of the deletion of the target region was determined by the size of the amplification product, and the genetic line was determined from the result. EAI strain is RD239 (-) and TbD1 (+), Beijing strain is RD105 (-) and TbD1 (-), CAS strain is RD750 (-) and TbD1 (-), Euro-American strain is TbD1 (-) and 7 bp deletion at pks 15/1. The other strains were TbD1 (-) and all other four regions (+). Classification was also performed by spoligotyping, but it was consistent with the classification result by the LSP method. All samples used this time were infected by a single genetic lineage. In the present invention, since Beijing (Beijing) strains are frequently infected, non-Beijing strains are collectively referred to as non-Beijing strains, and non-Beijing strains are classified as EAI strains, CAS strains and Euro-American strains. Is included. Similarly, since the EAI strain is frequently infected, strains other than the EAI strain are collectively referred to as non-EAI strains, and non-EAI strains include Beijing strains, CAS strains and Euro-American strains.
　それらの感染している結核菌のゲノム情報をもとに、北京株感染患者群、非北京株感染患者群、EAI株感染患者群、非EAI株感染患者群それぞれに結核症全患者群を分類し、共通の遺伝系統の結核菌に感染した患者群と対照となる健常者群における266,604SNPｓのアリル頻度を比較する関連解析を実施することで、結核菌の遺伝系統と特異的な関連が示唆されるSNPsを同定した。同時に、患者の発症年齢情報を用いての患者群の分類も組み合わせた解析により共通の発症機構を有していると考えられる患者群を抽出し、結核菌の遺伝系統と特定の発症年齢において特異的な関連が示唆されるSNPsを同定した。患者の発症年齢による分類は既報（Mahasirimongkol S et al. J Hum Genet. 2012 Jun;57(6):363-7）に従い45歳以上の老年発症群と45歳未満の若年発症群に分類した。本探索により見出された結核菌の遺伝系統特異的に結核症発症と関連するSNPｓ及びその近傍遺伝子が発明の具体的な対象となる（図１～４）。 Based on the genome information of these infected tuberculosis bacteria, we classify the whole group of patients with tuberculosis among the patients infected with Beijing stock, those infected with non-Beijing stock, those infected with EAI, and those infected with non EAI stock. By performing association analysis comparing allele frequencies of 266, 604 SNPs in a group of patients infected with M. tuberculosis, a common genetic lineage, and a group of control healthy people, a specific association with M. tuberculosis's lineage is suggested Identified SNPs. At the same time, a combination of classification of patient groups using patient onset age information is combined to analyze a group of patients considered to have a common onset mechanism, and is unique at the genetic lineage of M. tuberculosis and at a specific onset age We identified SNPs that suggest a specific relationship. The patients were classified according to their age of onset according to the previous report (Mahasirimongkol S et al. J Hum Genet. 2012 Jun; 57 (6): 363-7) according to age group older than 45 and younger group younger than 45 years. The genetic strains of M. tuberculosis found by this search specifically include SNPs associated with the onset of tuberculosis and genes in the vicinity thereof (FIG. 1 to 4).
　関連解析においては結核患者群と健常者群の間でアリルのカウントについてカイ二乗検定を行い、P値を算出している。結核患者群と健常者群の間での遺伝的背景のズレの指標であるgenomic inflation factorは1.066と許容範囲内であった。統計的にP値が1E-05を下回るものは関連が示唆されたもの(suggestively associated)と判断される。P値が1E-05を下回った全てのSNPsについて遺伝子型タイピングの生データの確認を行い、遺伝子型決定に問題が無いことを確認している。 In association analysis, chi-square test is performed on counts of alleles between a group of tuberculosis patients and a group of healthy subjects to calculate P values. The genomic inflation factor, which is an indicator of genetic background gap between TB patients and healthy people, was within the acceptable range of 1.066. Statistically, P values lower than 1E-05 are judged to be suggested associated (suggestively associated). The raw data of genotyping was confirmed for all SNPs whose P value was less than 1E-05, and it was confirmed that there was no problem in genotyping.
　具体的な結果としては、収集された集団中の北京株感染患者群において、結核菌の遺伝系統情報を考慮しない全患者群（表中Totalの欄)に比べて検体数が少ないにも関わらずより統計的に有意な関連（P値）が見出されるSNPsが14個同定された。これらのSNPｓは非北京株感染患者群においては有意な関連が見出されなかった。これら14SNPsの最近傍の遺伝子として10種の遺伝子が見出された（表中Geneの項目)。その他の分類においても、非北京株感染患者群において全患者群よりも有意な関連を示す12SNPs(11遺伝子）、EAI株感染患者群において全患者群よりも有意な関連を示す8SNPs(6遺伝子）、非EAI株感染患者群において全患者群よりも有意な関連を示す5SNPs（5遺伝子）が同定された。 As a specific result, the number of specimens in the group of patients infected with the strain of Beijing stock in the collected population is smaller than that in the group of all patients who do not consider M. tuberculosis genetic line information (the column of Total in the table). Fourteen SNPs were identified for which more statistically significant associations (P values) were found. These SNPs did not find significant association in the non-Beijing strain-infected patient group. Ten genes were found as the nearest genes to these 14 SNPs (in the table, Gene items). Also in the other classifications, 12 SNPs (11 genes) showing more significant association than non-Beijing strain infected patient group than all patient groups, 8 SNPs (6 genes) showing more significant association than all patient groups in EAI strain infected patient group 5 SNPs (5 genes) were identified that showed more significant association than non-EAI infected patients than all patients.
　また、各結核発症リスク候補遺伝子の結核患者における発現解析を、既報（Berry MP et al. Nature. 2010 Aug 19;466(7309):973-7.）のGene Expression Omnibus登録データ(GSE19435及びGSE19439)を用いて行った。このデータはUnited Kingdom在住の結核患者の血液よりRNAを回収し、Illumina Human HT-12 V3 BeadChip arrays (Illumina)による発現量測定を行ったものである。Illumina BeadStudio version 1.5.1.3ソフトウェアを用いてアレイ間のデータの均一化が既に行われたデータとして公開されている。データに付随して公開されている発現量の信頼性の指標であるdetection p-valueが0.05以下と十分に信頼性のあるデータを解析に使用した。その結果、CD53遺伝子とMAFB遺伝子それぞれについて、健常者（Control）に比べ患者（治療開始前）（PTB_00）で遺伝子発現量が有意に上昇しており、治療後2ヶ月（PTB_02）、12ヶ月（PTB_12）の時点では発現量が低下していた。さらに、CD53遺伝子とMAFB遺伝子それぞれ、結核菌に感染しているものの発症していない潜在感染（Latent TB, LTB）の患者よりも、結核発症患者（Pulmonary TB, PTB）において遺伝子発現量が上昇していた。図５にCD53遺伝子の結果、図６にMAFB遺伝子の結果を示す。それぞれの図においてＡは、健常者（Control）、患者（治療開始前, PTB_00）、治療後2ヶ月（PTB_02）及び12ヶ月（PTB_12）の時点での発現量を示し、Ｂは健常者（Control）、結核菌感染未発症者（潜伏感染）（LTB)及び（結核発症患者）(PTB)における発現量を示す。本解析では結核菌の遺伝系統は考慮できていないものの、近傍のSNPにおいて結核菌遺伝系統特異的な発症リスクが見られることを合わせると、これらの遺伝子発現量の上昇を測定することは、結核発症の予測に有用なマーカーとなる可能性がある。 In addition, the expression analysis of each tuberculosis onset risk candidate gene in tuberculosis patients was published (Berry MP et al. Nature. 2010 Aug 19; 466 (7309): 973-7.) Gene Expression Omnibus registration data (GSE 19435 and GSE 19439) Using the This data is obtained by collecting RNA from the blood of a tuberculosis patient living in United Kingdom, and measuring the expression level by Illumina Human HT-12 V3 BeadChip arrays (Illumina). Inter-array data equalization has been published as data that has already been performed using Illumina BeadStudio version 1.5.1.3 software. The data with sufficient detection p-value of 0.05 or less, which is an indicator of the reliability of the expression level published accompanying the data, was used for analysis. As a result, for the CD53 gene and the MAFB gene, the gene expression level is significantly increased in the patient (before the start of treatment) (PTB_00) compared to the healthy person (Control), 2 months after treatment (PTB_02), 12 months (PTB_02) At PTB_12), the expression level was reduced. Furthermore, the gene expression level of the CD53 gene and the MAFB gene is higher in patients with tuberculosis (Pulmonary TB, PTB) than in patients with latent infection (Latent TB, LTB) infected with but not developing tuberculosis. It was FIG. 5 shows the results of the CD53 gene, and FIG. 6 shows the results of the MAFB gene. In each figure, A indicates the expression level at healthy control (Control), patient (before treatment start, PTB_00), 2 months after treatment (PTB_02) and 12 months (PTB_12), and B indicates healthy people (Control) The expression levels in M. tuberculosis-infected patients (latent infection) (LTB) and (tuberculous onset patients) (PTB) are shown. Although the genetic lineage of M. tuberculosis can not be considered in this analysis, the increase in the expression level of these genes can be measured by combining the fact that the M. tuberculosis gene line-specific onset risk is observed in nearby SNPs. It may be a useful marker for predicting the onset.
　本発明の方法により、結核菌に感染している被験体において、結核菌の遺伝系統ごとに結核症を発症するリスクを判定することができ、結核症の発症の可能性の診断に利用することができる。
　本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられるものとする。 According to the method of the present invention, in a subject infected with Mycobacterium tuberculosis, the risk of developing tuberculosis can be determined for each genetic strain of Mycobacterium tuberculosis, and used for diagnosing the possibility of developing tuberculosis Can.
All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims (10)

  1. 　被験体において、結核症の発症と関連している被験体ゲノムの一塩基多型部位の塩基を同定し、かつ被験体に潜伏感染している結核菌遺伝系統をタイピングし、結核菌遺伝系統特異的に、被験体において潜伏感染している結核菌により結核症を発症するリスクを判定する方法。 In the subject, identify the base of the single nucleotide polymorphism site of the subject's genome that is associated with the onset of tuberculosis, and type the Mycobacterium tuberculosis gene line latently infected to the subject, A method of determining the risk of developing tuberculosis due to a latently infected M. tuberculosis in a subject.
  2. 　タイピングされる結核菌遺伝系統が、北京株、非北京株、EAI株及び非EAI株からなる群から選択される、請求項１記載の方法。 The method according to claim 1, wherein the M. tuberculosis genetic line to be typed is selected from the group consisting of Beijing strain, non-Beijing strain, EAI strain and non-EAI strain.
  3. 　被験体が感染している結核菌が北京株であるときに、以下の(b1)～(b14)の少なくとも１つの一塩基多型部位の塩基を同定し、被験体が感染している結核菌が非北京株であるときに、以下の(nb1)～(nb12)の少なくとも１つの一塩基多型部位の塩基を同定し、被験体が感染している結核菌がEAI株であるときに、以下の(e1)～(e8)の少なくとも１つの一塩基多型部位の塩基を同定し、被験体が感染している結核菌が非EAI株であるときに、以下の(ne1)～(ne5)の少なくとも１つの一塩基多型部位の塩基を同定することを含む、請求項１又は２に記載の方法：
    (b1)　rs9348878
    　配列番号１で示される塩基配列の26番目の塩基における多型であり、G又はAである；
    (b2)　rs2070600
    　配列番号２で示される塩基配列の26番目の塩基における多型であり、A又はGである；
    (b3)　rs401864
    　配列番号３で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (b4)　rs673119
    　配列番号４で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (b5)　rs1321267
    　配列番号５で示される塩基配列の26番目の塩基における多型であり、C又はAである；
    (b6)　rs2076625
    　配列番号６で示される塩基配列の26番目の塩基における多型であり、G又はTである；
    (b7)　rs7142055
    　配列番号７で示される塩基配列の26番目の塩基における多型であり、T又はCである；
    (b8)　rs1157619
    　配列番号８で示される塩基配列の26番目の塩基における多型であり、T又はCである；
    (b9)　rs4924568
    　配列番号９で示される塩基配列の26番目の塩基における多型であり、A又はGである；
    (b10)　rs1899820
    　配列番号10で示される塩基配列の26番目の塩基における多型であり、A又はCである；
    (b11)　rs2695163
    　配列番号11で示される塩基配列の26番目の塩基における多型であり、G又はAである；
    (b12)　rs1197772
    　配列番号12で示される塩基配列の26番目の塩基における多型であり、G又はAである；
    (b13)　rs1081022
    　配列番号13で示される塩基配列の26番目の塩基における多型であり、T又はGである；
    (b14)　rs1648835
    　配列番号14で示される塩基配列の26番目の塩基における多型であり、T又はGである；
    (nb1)　rs12144738
    　配列番号15で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (nb2)　rs1494320
    　配列番号16で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (nb3)　rs1712674
    　配列番号17で示される塩基配列の26番目の塩基における多型であり、G又はTである；
    (nb4)　rs1418425
    　配列番号18で示される塩基配列の26番目の塩基における多型であり、T又はCである；
    (nb5)　rs4688637
    　配列番号19で示される塩基配列の26番目の塩基における多型であり、C又はAである；
    (nb6)　rs12374531
    　配列番号20で示される塩基配列の26番目の塩基における多型であり、G又はAである；
    (nb7)　rs11784415
    　配列番号21で示される塩基配列の26番目の塩基における多型であり、C又はAである；
    (nb8)　rs2182093
    　配列番号22で示される塩基配列の26番目の塩基における多型であり、T又はCである；
    (nb9)　rs10798
    　配列番号23で示される塩基配列の26番目の塩基における多型であり、A又はGである；
    (nb10)　rs4267316
    　配列番号24で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (nb11)　rs6071980
    　配列番号25で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (nb12)　rs743057
    　配列番号26で示される塩基配列の26番目の塩基における多型であり、A又はGである；
    (e1)　rs1178938
    　配列番号27で示される塩基配列の26番目の塩基における多型であり、C又はAである；
    (e2)　rs800065
    　配列番号28で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (e3)　rs1372667
    　配列番号29で示される塩基配列の26番目の塩基における多型であり、G又はTである；
    (e4)　rs13174549
    　配列番号30で示される塩基配列の26番目の塩基における多型であり、T又はCである；
    (e5)　rs7087410
    　配列番号31で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (e6)　rs10898382
    　配列番号32で示される塩基配列の26番目の塩基における多型であり、A又はCである；
    (e7)　rs957129
    　配列番号33で示される塩基配列の26番目の塩基における多型であり、A又はCである；
    (e8)　rs1658693
    　配列番号34で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (ne1)　rs1820920
    　配列番号35で示される塩基配列の26番目の塩基における多型であり、C又はTである；
    (ne2)　rs11737270
    　配列番号36で示される塩基配列の26番目の塩基における多型であり、G又はAである；
     (ne3)　rs10832678
    　配列番号37で示される塩基配列の26番目の塩基における多型であり、G又はAである；
    (ne4)　rs10507084
    　配列番号38で示される塩基配列の26番目の塩基における多型であり、T又はCである；又は
    (ne5)　rs1440548
    　配列番号39で示される塩基配列の26番目の塩基における多型であり、C又はTである。     When the tubercle bacillus in which the subject is infected is a Beijing strain, the base of at least one single nucleotide polymorphism site of the following (b1) to (b14) is identified, and the tubercle bacillus in which the subject is infected: When the is a non-Beijing strain, the base of at least one single nucleotide polymorphism site of the following (nb1) to (nb12) is identified, and the Mycobacterium tuberculosis with which the subject is infected is the EAI strain: When the base of at least one single nucleotide polymorphism site of the following (e1) to (e8) is identified, and the Mycobacterium tuberculosis with which the subject is infected is a non-EAI strain, the following (ne1) to (ne5) The method according to claim 1 or 2, comprising identifying a base of at least one single nucleotide polymorphism site of
    (b1) rs9348878
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 1, G or A;
    (b2) rs2070600
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 2, which is A or G;
    (b3) rs401864
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 3, C or T;
    (b4) rs673119
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 4 and is C or T;
    (b5) rs1321267
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 5, which is C or A;
    (b6) rs2076625
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 6, which is G or T;
    (b7) rs7142055
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 7 and T or C;
    (b8) rs1157619
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 8 and T or C;
    (b9) rs4924568
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 9 and is A or G;
    (b10) rs1899820
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 10, which is A or C;
    (b11) rs2695163
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 11, G or A;
    (b12) rs1197772
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 12 and G or A;
    (b13) rs1081022
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 13 and T or G;
    (b14) rs 1648835
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 14 and T or G;
    (nb1) rs12144738
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 15, C or T;
    (nb2) rs1494320
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 16, which is C or T;
    (nb3) rs1712674
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 17, G or T;
    (nb4) rs1418425
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 18, which is T or C;
    (nb5) rs4688637
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 19 and is C or A;
    (nb6) rs12374531
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 20, which is G or A;
    (nb7) rs11784415
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 21, which is C or A;
    (nb8) rs2182093
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 22, which is T or C;
    (nb9) rs10798
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 23, which is A or G;
    (nb10) rs4267316
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 24, C or T;
    (nb11) rs6071980
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 25 and is C or T;
    (nb12) rs743057
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 26, which is A or G;
    (e1) rs1178938
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 27 and is C or A;
    (e2) rs800065
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 28 and is C or T;
    (e3) rs1372667
    Polymorphism at base 26 of the base sequence shown in SEQ ID NO: 29, G or T;
    (e4) rs13174549
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 30, which is T or C;
    (e5) rs7087410
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 31, which is C or T;
    (e6) rs10898382
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 32, and is A or C;
    (e7) rs957129
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 33, which is A or C;
    (e8) rs1658693
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 34, which is C or T;
    (ne1) rs1820920
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 35, which is C or T;
    (ne2) rs11737270
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 36, which is G or A;
    (ne3) rs10832678
    Polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 37, which is G or A;
    (ne4) rs10507084
    Polymorphism at the 26th base of the base sequence shown in SEQ ID NO: 38, T or C; or
    (ne5) rs1440548
    The polymorphism at the 26th base of the base sequence shown by SEQ ID NO: 39, which is C or T.
  4. （１）　配列番号１で示される塩基配列の26番目の一塩基多型部位（(b1)　rs9348878）の塩基がGの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （２）　配列番号２で示される塩基配列の26番目の一塩基多型部位（(b2)　rs2070600）の塩基がAの場合に、Gの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （３）　配列番号３で示される塩基配列の26番目の一塩基多型部位（(b3)　rs401864）の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
    （４）　配列番号４で示される塩基配列の26番目の一塩基多型部位（(b4)　rs673119）の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （５）　配列番号５で示される塩基配列の26番目の一塩基多型部位（(b5)　rs1321267）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （６）　配列番号６で示される塩基配列の26番目の一塩基多型部位（(b6)　rs2076625）の塩基がGの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが低いと判定し、
    （７）　配列番号７で示される塩基配列の26番目の一塩基多型部位（(b7)　rs7142055）の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （８）　配列番号８で示される塩基配列の26番目の一塩基多型部位（(b8)　rs1157619）の塩基がTの場合に、Cの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
    （９）　配列番号９で示される塩基配列の26番目の一塩基多型部位（(b9)　rs4924568）の塩基がAの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （10）　配列番号10で示される塩基配列の26番目の一塩基多型部位（(b10)　rs1899820）の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （11）　配列番号11で示される塩基配列の26番目の一塩基多型部位（(b11)　rs2695163）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （12）　配列番号12で示される塩基配列の26番目の一塩基多型部位（(b12)　rs1197772）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （13）　配列番号13で示される塩基配列の26番目の一塩基多型部位（(b13)　rs1081022）の塩基がTの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （14）　配列番号14で示される塩基配列の26番目の一塩基多型部位（(b14)　rs1648835）の塩基がTの場合に、Gの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （15）　配列番号15で示される塩基配列の26番目の一塩基多型部位（(nb1)　rs12144738）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （16）　配列番号16で示される塩基配列の26番目の一塩基多型部位（(nb2)　rs1494320）の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （17）　配列番号17で示される塩基配列の26番目の一塩基多型部位（(nb3)　rs1712674）の塩基がGの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （18）　配列番号18で示される塩基配列の26番目の一塩基多型部位（(nb4)　rs1418425）の塩基がTの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （19）　配列番号19で示される塩基配列の26番目の一塩基多型部位（(nb5)　rs4688637）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （20）　配列番号20で示される塩基配列の26番目の一塩基多型部位（(nb6)　rs12374531）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが低いと判定し、
    （21）　配列番号21で示される塩基配列の26番目の一塩基多型部位（(nb7)　rs11784415）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （22）　配列番号22で示される塩基配列の26番目の一塩基多型部位（(nb8)　rs2182093）の塩基がTの場合に、Cの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （23）　配列番号23で示される塩基配列の26番目の一塩基多型部位（(nb9)　rs10798）の塩基がAの場合に、Gの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
    （24）　配列番号24で示される塩基配列の26番目の一塩基多型部位（(nb10)　rs4267316）の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定し、
    （25）　配列番号25で示される塩基配列の26番目の一塩基多型部位（(nb11)　rs6071980）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （26）　配列番号26で示される塩基配列の26番目の一塩基多型部位（(nb12)　rs743057）の塩基がAの場合に、Gの場合に比べあらゆる年齢において結核症を発症するリスクが低いと判定し、
    （27）　配列番号27で示される塩基配列の26番目の一塩基多型部位（(e1)　rs1178938）の塩基がCの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （28）　配列番号28で示される塩基配列の26番目の一塩基多型部位（(e2)　rs800065）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （29）　配列番号29で示される塩基配列の26番目の一塩基多型部位（(e3)　rs1372667）の塩基がGの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （30）　配列番号30で示される塩基配列の26番目の一塩基多型部位（(e4)　rs13174549）の塩基がTの場合に、Cの場合に比べあらゆる年齢において結核症を発症するリスクが低いと判定し、
    （31）　配列番号31で示される塩基配列の26番目の一塩基多型部位（(e5)　rs7087410）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （32）　配列番号32で示される塩基配列の26番目の一塩基多型部位（(e6)　rs10898382）の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （33）　配列番号33で示される塩基配列の26番目の一塩基多型部位（(e7)　rs951729）の塩基がAの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （34）　配列番号34で示される塩基配列の26番目の一塩基多型部位（(e8)　rs1658693）の塩基がCの場合に、Tの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが低いと判定し、
    （35）　配列番号35で示される塩基配列の26番目の一塩基多型部位（(ne1)　rs1820920）の塩基がCの場合に、Tの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （36）　配列番号36で示される塩基配列の26番目の一塩基多型部位（(ne2)　rs11737270）の塩基がGの場合に、Aの場合に比べ若年期（４５歳未満）において結核症を発症するリスクが高いと判定し、
    （37）　配列番号37で示される塩基配列の26番目の一塩基多型部位（(ne3)　rs10832678）の塩基がGの場合に、Aの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが高いと判定し、
    （38）　配列番号38で示される塩基配列の26番目の一塩基多型部位（(ne4)　rs10507084）の塩基がTの場合に、Cの場合に比べ老年期（４５歳以上）において結核症を発症するリスクが低いと判定し、
    （39）　配列番号39で示される塩基配列の26番目の一塩基多型部位（(ne5)　rs1440548）の塩基がCの場合に、Tの場合に比べあらゆる年齢において結核症を発症するリスクが高いと判定する、
    請求項３記載の方法。     (1) When the base of the 26th single nucleotide polymorphism site ((b1) rs9348878) of the base sequence shown in SEQ ID NO: 1 is G, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
    (2) When the base of the 26th single nucleotide polymorphism site ((b2) rs2070600) of the base sequence shown in SEQ ID NO: 2 is A, tuberculosis is younger than in the case of G (at less than 45 years of age) It is judged that the risk of developing is high,
    (3) When the base of the 26th single nucleotide polymorphism site ((b3) rs401864) of the base sequence shown in SEQ ID NO: 3 is C, the risk of developing tuberculosis at any age is higher than in the case of T Determined as
    (4) When the base of the 26th single nucleotide polymorphism site ((b4) rs673119) of the base sequence shown in SEQ ID NO: 4 is C, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is high,
    (5) When the base of the 26th single nucleotide polymorphism site ((b5) rs1321267) of the base sequence shown in SEQ ID NO: 5 is C, tuberculosis is younger than in the case of A (less than 45 years of age) It is judged that the risk of developing is high,
    (6) When the base of the 26th single nucleotide polymorphism site ((b6) rs2076625) of the nucleotide sequence shown in SEQ ID NO: 6 is G, the risk of developing tuberculosis at any age is lower than in T. Determined as
    (7) When the base of the 26th single nucleotide polymorphism site ((b7) rs7142055) of the base sequence shown in SEQ ID NO: 7 is T, tuberculosis is younger than in the case of C (less than 45 years of age) It is judged that the risk of developing is high,
    (8) When the base of the 26th single nucleotide polymorphism site ((b8) rs1157619) of the base sequence shown in SEQ ID NO: 8 is T, the risk of developing tuberculosis at any age is higher than in the case of C Determined as
    (9) When the base of the 26th single nucleotide polymorphism site ((b9) rs4924568) of the base sequence shown in SEQ ID NO: 9 is A, tuberculosis is observed in old age (45 years or older) compared to G. It is judged that the risk of developing is high,
    (10) When the base of the 26th single nucleotide polymorphism site ((b10) rs1899820) of the base sequence shown in SEQ ID NO: 10 is A, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
    (11) When the base of the 26th single nucleotide polymorphism site ((b11) rs2695163) of the base sequence shown in SEQ ID NO: 11 is G, tuberculosis is observed in old age (45 years or older) as compared with A. It is judged that the risk of developing is high,
    (12) When the base of the 26th single nucleotide polymorphism site ((b12) rs1197772) of the base sequence shown in SEQ ID NO: 12 is G, tuberculosis is observed in old age (45 years or older) as compared with A. It is judged that the risk of developing is high,
    (13) When the base of the 26th single nucleotide polymorphism site ((b13) rs1081022) of the base sequence shown in SEQ ID NO: 13 is T, tuberculosis is observed in old age (45 years or older) compared to G. It is judged that the risk of developing is high,
    (14) When the base of the 26th single nucleotide polymorphism site ((b14) rs 1648835) of the base sequence shown in SEQ ID NO: 14 is T, tuberculosis is detected in old age (45 years or older) compared to G. It is judged that the risk of developing is high,
    (15) When the base of the 26th single nucleotide polymorphism site ((nb1) rs12144738) of the base sequence shown in SEQ ID NO: 15 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
    (16) When the base of the 26th single nucleotide polymorphism site ((nb2) rs1494320) of the base sequence shown in SEQ ID NO: 16 is C, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is high,
    (17) When the base of the 26th single nucleotide polymorphism site ((nb3) rs1712674) of the base sequence shown in SEQ ID NO: 17 is G, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is high,
    (18) When the base of the 26th single nucleotide polymorphism site ((nb 4) rs 1418425) of the base sequence shown by SEQ ID NO: 18 is T, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
    (19) When the base of the 26th single nucleotide polymorphism site ((nb5) rs4688637) of the base sequence shown in SEQ ID NO: 19 is C, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
    (20) Tuberculosis in old age (more than 45 years old) compared to the case of A when the base of the 26th single nucleotide polymorphism site ((nb6) rs12374531) of the base sequence shown in SEQ ID NO: 20 is G It is judged that the risk of developing is low.
    (21) When the base of the 26th single nucleotide polymorphism site ((nb7) rs11784415) of the base sequence shown by SEQ ID NO: 21 is C, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
    (22) When the base of the 26th single nucleotide polymorphism site ((nb8) rs2182093) of the base sequence shown in SEQ ID NO: 22 is T, tuberculosis is younger than in the case of C (less than 45 years of age) It is judged that the risk of developing is high,
    (23) When the base of the 26th single nucleotide polymorphism site ((nb9) rs10798) of the base sequence shown by SEQ ID NO: 23 is A, the risk of developing tuberculosis at any age is higher than in the case of G Determined as
    (24) When the 26th single nucleotide polymorphism site ((nb 10) rs 4267 316) of the nucleotide sequence shown in SEQ ID NO: 24 is C, the risk of developing tuberculosis at any age is higher than in T. Determined as
    (25) When the base of the 26th single nucleotide polymorphism site ((nb11) rs6071980) of the base sequence shown by SEQ ID NO: 25 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
    (26) When the base of the 26th single nucleotide polymorphism site ((nb12) rs743057) of the nucleotide sequence shown in SEQ ID NO: 26 is A, the risk of developing tuberculosis at any age is lower than in the case of G Determined as
    (27) When the base of the 26th single nucleotide polymorphism site ((e1) rs1178938) of the base sequence shown in SEQ ID NO: 27 is C, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
    (28) When the base of the 26th single nucleotide polymorphism site ((e2) rs8000065) of the base sequence shown in SEQ ID NO: 28 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
    (29) When the base of the 26th single nucleotide polymorphism site ((e3) rs1372667) in the nucleotide sequence shown in SEQ ID NO: 29 is G, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
    (30) When the base of the 26th single nucleotide polymorphism site ((e4) rs13174549) of the nucleotide sequence shown in SEQ ID NO: 30 is T, the risk of developing tuberculosis at any age is lower than in the case of C Determined as
    (31) When the base of the 26th single nucleotide polymorphism site ((e5) rs7087410) of the base sequence shown in SEQ ID NO: 31 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
    (32) When the base of the 26th single nucleotide polymorphism site ((e6) rs10898382) of the base sequence shown in SEQ ID NO: 32 is A, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
    (33) When the base of the 26th single nucleotide polymorphism site ((e7) rs951729) of the base sequence shown in SEQ ID NO: 33 is A, tuberculosis is detected in old age (45 years or older) compared to C. It is judged that the risk of developing is high,
    (34) When the base of the 26th single nucleotide polymorphism site ((e8) rs1658693) of the base sequence shown in SEQ ID NO: 34 is C, tuberculosis is observed in old age (45 years or older) compared to T. It is judged that the risk of developing is low.
    (35) When the base of the 26th single nucleotide polymorphism site ((ne1) rs1820920) of the base sequence shown in SEQ ID NO: 35 is C, tuberculosis is younger than in the case of T (less than 45 years of age) It is judged that the risk of developing is high,
    (36) When the base of the 26th single nucleotide polymorphism site ((ne2) rs11737270) of the base sequence shown in SEQ ID NO: 36 is G, tuberculosis is younger than in the case of A (at less than 45 years of age) It is judged that the risk of developing is high,
    (37) When the base of the 26th single nucleotide polymorphism site ((ne3) rs10832678) of the nucleotide sequence shown in SEQ ID NO: 37 is G, tuberculosis is detected in old age (45 years or older) as compared with A. It is judged that the risk of developing is high,
    (38) When the base of the 26th single nucleotide polymorphism site ((ne4) rs10507084) of the nucleotide sequence shown in SEQ ID NO: 38 is T, tuberculosis is observed in old age (45 years or older) compared to C. It is judged that the risk of developing is low.
    (39) When the base of the 26th single nucleotide polymorphism site ((ne5) rs1440548) of the nucleotide sequence shown in SEQ ID NO: 39 is C, the risk of developing tuberculosis at any age is higher than in the case of T To determine
    The method of claim 3.
  5. 　結核菌感染被験体における結核症発症のリスクを判定するためのプライマーであって、以下の(p1)～(p14)のいずれかの北京株感染被験体における結核症発症のリスクを判定するためのプライマー、以下の(p15)～(p26)のいずれかの非北京株感染被験体における結核症発症のリスクを判定するためのプライマー、以下の(p27)～(p34)のいずれかのEAI株感染被験体における結核症発症のリスクを判定するためのプライマー、又は以下の(p35)～(p39)のいずれかの非EAI株感染被験体における結核症発症のリスクを判定するためのプライマー：
    (p1)　配列番号１の塩基配列における26番目の塩基（rs9348878の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p2)　配列番号２の塩基配列における26番目の塩基（rs2070600の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p3)　配列番号３の塩基配列における26番目の塩基（rs401864の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p4)　配列番号４の塩基配列における26番目の塩基（rs673119の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p5)　配列番号５の塩基配列における26番目の塩基（rs1321267の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p6)　配列番号６の塩基配列における26番目の塩基（rs2076625の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p7)　配列番号７の塩基配列における26番目の塩基（rs7142055の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p8)　配列番号８の塩基配列における26番目の塩基（rs1157619の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p9)　配列番号９の塩基配列における26番目の塩基（rs4924568の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p10)　配列番号10の塩基配列における26番目の塩基（rs1899820の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p11)　配列番号11の塩基配列における26番目の塩基（rs2695163の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p12)　配列番号12の塩基配列における26番目の塩基（rs1197772の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p13)　配列番号13の塩基配列における26番目の塩基（rs1081022の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p14)　配列番号14の塩基配列における26番目の塩基（rs1648835の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p15)　配列番号15の塩基配列における26番目の塩基（rs12144738の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p16)　配列番号16の塩基配列における26番目の塩基（rs1494320の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p17)　配列番号17の塩基配列における26番目の塩基（rs1712674の多型部位の塩基）を含む領域を増幅することができるプライマー
    (p18)　配列番号18の塩基配列における26番目の塩基（rs1418425の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p19)　配列番号19の塩基配列における26番目の塩基（rs4688637の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p20)　配列番号20の塩基配列における26番目の塩基（rs12374531の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p21)　配列番号21の塩基配列における26番目の塩基（rs11784415の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p22)　配列番号22の塩基配列における26番目の塩基（rs2182093の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p23)　配列番号23の塩基配列における26番目の塩基（rs10798の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p24)　配列番号24の塩基配列における26番目の塩基（rs4267316の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p25)　配列番号25の塩基配列における26番目の塩基（rs6071980の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p26)　配列番号26の塩基配列における26番目の塩基（rs743057の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p27)　配列番号27の塩基配列における26番目の塩基（rs1178938の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p28)　配列番号28の塩基配列における26番目の塩基（rs800065の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p29)　配列番号29の塩基配列における26番目の塩基（rs1372667の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p30)　配列番号30の塩基配列における26番目の塩基（rs13174549の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p31)　配列番号31の塩基配列における26番目の塩基（rs7087410の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p32)　配列番号32の塩基配列における26番目の塩基（rs10898382の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p33)　配列番号33の塩基配列における26番目の塩基（rs951729の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p34)　配列番号34の塩基配列における26番目の塩基（rs1658693の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p35)　配列番号35の塩基配列における26番目の塩基（rs1820920の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p36)　配列番号36の塩基配列における26番目の塩基（rs11737270の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p37)　配列番号37の塩基配列における26番目の塩基（rs10832678の多型部位の塩基）を含む領域を増幅することができるプライマー；
    (p38)　配列番号38の塩基配列における26番目の塩基（rs10507084の多型部位の塩基）を含む領域を増幅することができるプライマー；又は
    (p39)　配列番号39の塩基配列における26番目の塩基（rs1440548の多型部位の塩基）を含む領域を増幅することができるプライマー。     A primer for determining the risk of developing tuberculosis in a Mycobacterium tuberculosis-infected subject, which is for determining the risk of developing tuberculosis in a Beijing-strain-infected subject according to any of the following (p1) to (p14): Primer, a primer for determining the risk of developing tuberculosis in a non-Beijing strain-infected subject according to any of the following (p15) to (p26), an EAI strain infection according to any of the following (p27) to (p34): Primers for determining the risk of developing tuberculosis in a subject, or primers for determining the risk of developing tuberculosis in a non-EAI infected subject having any of the following (p35) to (p39):
    (p1) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs9348878) in the base sequence of SEQ ID NO: 1;
    (p2) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs2070600) in the nucleotide sequence of SEQ ID NO: 2;
    (p3) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs401864) in the base sequence of SEQ ID NO: 3;
    (p4) a primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs673119) in the base sequence of SEQ ID NO: 4;
    (p5) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1321267) in the base sequence of SEQ ID NO: 5;
    (p6) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs2076625) in the base sequence of SEQ ID NO: 6;
    (p7) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs7142055) in the nucleotide sequence of SEQ ID NO: 7;
    (p8) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1157619) in the nucleotide sequence of SEQ ID NO: 8;
    (p9) A primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs4924568) in the base sequence of SEQ ID NO: 9;
    (p10) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1899820) in the base sequence of SEQ ID NO: 10;
    (p11) a primer capable of amplifying a region containing the 26th base (the base of polymorphic site of rs2695163) in the base sequence of SEQ ID NO: 11;
    (p12) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1197772) in the nucleotide sequence of SEQ ID NO: 12;
    (p13) a primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1081022) in the nucleotide sequence of SEQ ID NO: 13;
    (p14) A primer capable of amplifying a region containing the 26th base (a base at polymorphic site of rs1648835) in the nucleotide sequence of SEQ ID NO: 14;
    (p15) A primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs12144738) in the nucleotide sequence of SEQ ID NO: 15;
    (p16) a primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16;
    (p17) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1712674) in the nucleotide sequence of SEQ ID NO: 17
    (p18) A primer capable of amplifying a region including the 26th base (a base at a polymorphic site of rs1418425) in the nucleotide sequence of SEQ ID NO: 18;
    (p19) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs4688637) in the nucleotide sequence of SEQ ID NO: 19;
    (p20) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs12374531) in the nucleotide sequence of SEQ ID NO: 20;
    (p21) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs11784415) in the nucleotide sequence of SEQ ID NO: 21;
    (p22) a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs2182093) in the nucleotide sequence of SEQ ID NO: 22;
    (p23) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs10798) in the base sequence of SEQ ID NO: 23;
    (p24) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs4267316) in the nucleotide sequence of SEQ ID NO: 24;
    (p25) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs6071980) in the nucleotide sequence of SEQ ID NO: 25;
    (p26) A primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs743057) in the nucleotide sequence of SEQ ID NO: 26;
    (p27) a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27;
    (p28) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs8000065) in the nucleotide sequence of SEQ ID NO: 28;
    (p29) A primer capable of amplifying a region including the 26th base (a base at polymorphic site of rs1372667) in the nucleotide sequence of SEQ ID NO: 29;
    (p30) A primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs13174549) in the nucleotide sequence of SEQ ID NO: 30;
    (p31) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs7087410) in the base sequence of SEQ ID NO: 31;
    (p32) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs10898382) in the nucleotide sequence of SEQ ID NO: 32;
    (p33) a primer capable of amplifying a region containing the 26th base (a base at a polymorphic site of rs951729) in the base sequence of SEQ ID NO: 33;
    (p34) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1658693) in the nucleotide sequence of SEQ ID NO: 34;
    (p35) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1820920) in the nucleotide sequence of SEQ ID NO: 35;
    (p36) a primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs11737270) in the nucleotide sequence of SEQ ID NO: 36;
    (p37) A primer capable of amplifying a region containing the 26th base (base of polymorphic site of rs10832678) in the nucleotide sequence of SEQ ID NO: 37;
    (p38) a primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs10507084) in the base sequence of SEQ ID NO: 38; or
    (p39) A primer capable of amplifying a region containing the 26th base (a base of polymorphic site of rs1440548) in the nucleotide sequence of SEQ ID NO: 39.
  6. 　結核菌感染被験体における結核症発症のリスクを判定するためのプローブであって、
    以下の(q1)～(q14)のいずれかの北京株感染被験体における結核症発症のリスクを判定するためのプローブ、以下の(q15)～(q26)のいずれかの非北京株感染被験体における結核症発症のリスクを判定するためのプローブ、以下の(q27)～(q34)のいずれかのEAI株感染被験体における結核症発症のリスクを判定するためのプローブ、又は以下の(q35)～(q39)のいずれかの非EAI株感染被験体における結核症発症のリスクを判定するためのプローブ：(q1)　配列番号１の塩基配列における26番目の塩基（rs9348878の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q2)　配列番号２の塩基配列における26番目の塩基（rs2070600の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q3)　配列番号３の塩基配列における26番目の塩基（rs401864の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q4)　配列番号４の塩基配列における26番目の塩基（rs673119の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q5)　配列番号５の塩基配列における26番目の塩基（rs1321267の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q6)　配列番号６の塩基配列における26番目の塩基（rs2076625の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q7)　配列番号７の塩基配列における26番目の塩基（rs7142055の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q8)　配列番号８の塩基配列における26番目の塩基（rs1157619の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q9)　配列番号９の塩基配列における26番目の塩基（rs4924568の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q10)　配列番号10の塩基配列における26番目の塩基（rs1899820の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q11)　配列番号11の塩基配列における26番目の塩基（rs2695163の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q12)　配列番号12の塩基配列における26番目の塩基（rs1197772の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q13)　配列番号13の塩基配列における26番目の塩基（rs1081022の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q14)　配列番号14の塩基配列における26番目の塩基（rs1648835の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q15)　配列番号15の塩基配列における26番目の塩基（rs12144738の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q16)　配列番号16の塩基配列における26番目の塩基（rs1494320の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q17)　配列番号17の塩基配列における26番目の塩基（rs1712674の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q18)　配列番号18の塩基配列における26番目の塩基（rs1418425の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q19)　配列番号19の塩基配列における26番目の塩基（rs4688637の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q20)　配列番号20の塩基配列における26番目の塩基（rs12374531の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q21)　配列番号21の塩基配列における26番目の塩基（rs11784415の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q22)　配列番号22の塩基配列における26番目の塩基（rs2182093の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q23)　配列番号23の塩基配列における26番目の塩基（rs10798の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q24)　配列番号24の塩基配列における26番目の塩基（rs4267316の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q25)　配列番号25の塩基配列における26番目の塩基（rs6071980の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q26)　配列番号26の塩基配列における26番目の塩基（rs743057の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q27)　配列番号27の塩基配列における26番目の塩基（rs1178938の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q28)　配列番号28の塩基配列における26番目の塩基（rs800065の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q29)　配列番号29の塩基配列における26番目の塩基（rs1372667の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q30)　配列番号30の塩基配列における26番目の塩基（rs13174549の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q31)　配列番号31の塩基配列における26番目の塩基（rs7087410の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q32)　配列番号32の塩基配列における26番目の塩基（rs10898382の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q33)　配列番号33の塩基配列における26番目の塩基（rs951729の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q34)　配列番号34の塩基配列における26番目の塩基（rs1658693の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q35)　配列番号35の塩基配列における26番目の塩基（rs1820920の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q36)　配列番号36の塩基配列における26番目の塩基（rs11737270の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q37)　配列番号37の塩基配列における26番目の塩基（rs10832678の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ；
    (q38)　配列番号38の塩基配列における26番目の塩基（rs10507084の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ;又は
    (q39)　配列番号39の塩基配列における26番目の塩基（rs1440548の多型部位の塩基）を含む領域にハイブリダイズすることができるプローブ。     A probe for determining the risk of developing tuberculosis in a T. tuberculosis-infected subject, comprising
    A probe for determining the risk of developing tuberculosis in a Beijing strain-infected subject according to any of the following (q1) to (q14), a non-Beijing strain-infected subject according to any of the following (q15) to (q26): A probe for determining the risk of developing tuberculosis or a probe for determining the risk of developing tuberculosis in a subject infected with any of the EAI strains described in (q27) to (q34) below or (q35) A probe for determining the risk of developing tuberculosis in a non-EAI strain-infected subject of any of (q39): (q1) the 26th base in the base sequence of SEQ ID NO: 1 (base at polymorphic site of rs9348878) A probe capable of hybridizing to a region comprising
    (q2) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 2 (the base of polymorphic site of rs2070600);
    (q3) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 3 (a base of polymorphic site of rs401864);
    (q4) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs673119) in the base sequence of SEQ ID NO: 4;
    (q5) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1321267) in the base sequence of SEQ ID NO: 5;
    (q6) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs2076625) in the base sequence of SEQ ID NO: 6;
    (q7) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 7 (a base at polymorphic site of rs7142055);
    (q8) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1157619) in the base sequence of SEQ ID NO: 8;
    (q9) a probe capable of hybridizing to a region including the 26th base (a base at a polymorphic site of rs4924568) in the base sequence of SEQ ID NO: 9;
    (q10) a probe capable of hybridizing to a region containing the 26th base (a base at polymorphic site of rs1899820) in the base sequence of SEQ ID NO: 10;
    (q11) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs2695163) in the nucleotide sequence of SEQ ID NO: 11;
    (q12) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs1197772) in the base sequence of SEQ ID NO: 12;
    (q13) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1081022) in the base sequence of SEQ ID NO: 13;
    (q14) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs1648835) in the base sequence of SEQ ID NO: 14;
    (q15) a probe capable of hybridizing to a region including the 26th base (a base at a polymorphic site of rs12144738) in the base sequence of SEQ ID NO: 15;
    (q16) a probe capable of hybridizing to a region including the 26th base (a base at a polymorphic site of rs1494320) in the nucleotide sequence of SEQ ID NO: 16;
    (q17) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1712674) in the base sequence of SEQ ID NO: 17;
    (q18) a probe capable of hybridizing to a region containing the 26th base in the base sequence of SEQ ID NO: 18 (a base at polymorphic site of rs1418425);
    (q19) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs4688637) in the base sequence of SEQ ID NO: 19;
    (q20) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs12374531) in the nucleotide sequence of SEQ ID NO: 20;
    (q21) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 21 (a base at polymorphic site of rs11784415);
    (q22) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 22 (the base of polymorphic site of rs2182093);
    (q23) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs10798) in the base sequence of SEQ ID NO: 23;
    (q24) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 24 (a base at a polymorphic site of rs4267316);
    (q25) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs6071980) in the base sequence of SEQ ID NO: 25;
    (q26) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs743057) in the base sequence of SEQ ID NO: 26;
    (q27) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs1178938) in the nucleotide sequence of SEQ ID NO: 27;
    (q28) a probe capable of hybridizing to a region including the 26th base in the base sequence of SEQ ID NO: 28 (the base of polymorphic site of rs8000065);
    (q29) a probe capable of hybridizing to a region containing the 26th base (a base at polymorphic site of rs1372667) in the base sequence of SEQ ID NO: 29;
    (q30) a probe capable of hybridizing to a region containing a 26th base (a base at a polymorphic site of rs13174549) in the base sequence of SEQ ID NO: 30;
    (q31) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs7087410) in the nucleotide sequence of SEQ ID NO: 31;
    (q32) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10898382) in the nucleotide sequence of SEQ ID NO: 32;
    (q33) a probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs951729) in the base sequence of SEQ ID NO: 33;
    (q34) a probe capable of hybridizing to a region containing a 26th base (a base at a polymorphic site of rs1658693) in the base sequence of SEQ ID NO: 34;
    (q35) a probe capable of hybridizing to a region including the 26th base (a base of polymorphic site of rs1820920) in the base sequence of SEQ ID NO: 35;
    (q36) a probe capable of hybridizing to a region including the 26th base in the nucleotide sequence of SEQ ID NO: 36 (a base at polymorphic site of rs11737270);
    (q37) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10832678) in the base sequence of SEQ ID NO: 37;
    (q38) a probe capable of hybridizing to a region containing the 26th base (the base of polymorphic site of rs10507084) in the base sequence of SEQ ID NO: 38; or
    (q39) A probe capable of hybridizing to a region including the 26th base (a base at polymorphic site of rs 1440548) in the base sequence of SEQ ID NO: 39.
  7. 　請求項５に記載のプライマー又は請求項６に記載のプローブを含む、結核症を発症するリスクを判定するためのキット。 A kit for determining the risk of developing tuberculosis, comprising the primer according to claim 5 or the probe according to claim 6.
  8. 　被験体において、結核症の発症と関連している被験体ゲノムの一塩基多型部位の近傍に位置する遺伝子の発現量を測定し、かつ被験体に潜伏感染している結核菌遺伝系統をタイピングし、被験体において潜伏感染している結核菌により結核症を発症するリスクを判定する方法。 In the subject, measure the expression level of a gene located in the vicinity of a single nucleotide polymorphism site of the subject's genome that is associated with the onset of tuberculosis, and type in a latent infection with the T. tuberculosis genetic line in the subject And determining the risk of developing tuberculosis due to a latently infected M. tuberculosis in a subject.
  9. 　被験体が感染している結核菌が非北京株であるときに、配列番号16で示される塩基配列の26番目の塩基における一塩基多型（(nb2)　rs1494320）の近傍に位置する遺伝子であるCD53遺伝子の発現を測定し、該遺伝子の発現が上昇している場合に、結核症の発症のリスクが高いと判定する、請求項８記載の方法。 A gene located in the vicinity of a single nucleotide polymorphism ((nb2) rs1494320) at the 26th base of the nucleotide sequence shown in SEQ ID NO: 16 when the M. tuberculosis organism with which the subject is infected is a non-Beijing strain The method according to claim 8, wherein the expression of the CD53 gene is measured, and if the expression of the gene is elevated, the risk of developing tuberculosis is determined to be high.
  10. 　被験体が感染している結核菌が非北京株であるときに、配列番号25で示される塩基配列の26番目の塩基における一塩基多型（(nb11)　rs6071980）の近傍に位置する遺伝子であるMAFB遺伝子の発現を測定し、該遺伝子の発現が上昇している場合に、結核症の発症のリスクが高いと判定する、請求項８記載の方法。 A gene located in the vicinity of a single nucleotide polymorphism ((nb11) rs6071980) at the 26th base of the nucleotide sequence shown in SEQ ID NO: 25 when the tuberculosis bacterium with which the subject is infected is a non-Beijing strain The method according to claim 8, wherein the expression of the MAFB gene is measured, and if the expression of the gene is elevated, the risk of developing tuberculosis is determined to be high.
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