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RESEARCH

結核研究
Research for Tuberculosis

We are conducting genome-wide analysis to identify the genetic host factors associated with the onset of tuberculosis.

研究背景

結核は世界三大感染症のひとつであり、現在でも世界で年間1,000万人以上が新規に発症し、160万以上が死亡している疾患です。日本においても、年間約2万人が新規に発症しています。結核菌は世界で約4人に1人の体内に感染していますが、生涯の発症率は10％であり、宿主側の遺伝要因の寄与が示唆されています。

研究アプローチ

我々は、結核の発症に関わる宿主の遺伝要因を明らかにするため、人類遺伝学のアプローチからゲノム全域の解析を行っています。理化学研究所や結核予防会およびタイ保健省・マヒドン大学との共同研究により日本やタイ国で収集した患者ゲノムDNA試料と感染結核菌ゲノムDNA試料両方の解析を進めており、双方のDNA情報を用いての統合的な解析は世界的にも例が無く、我々独自のアプローチです。

主な成果

ゲノムワイドアプローチにより家族性結核における発症感受性遺伝子領域の同定や、若年性結核における発症感受性多型の同定を行いました。結核菌ゲノムの解析においても、我々独自の結核菌の遺伝子型決定法の開発を行っています。さらに、結核菌の遺伝子型の情報を組み込んだゲノムワイドアプローチにより、CD53やHLAが特定の遺伝子型をもつ結核菌感染時において発症と関連することを明らかにしました。また、抗結核薬による患者の肝障害についても、薬剤代謝酵素NAT2の特定の遺伝子型が発症と関連することを明らかにしました。

2014年度から2018年度まで、国立研究開発法人 科学技術振興機構（JST）および国立研究開発法人 日本医療研究開発機構（AMED)と独立行政法人 国際協力機構（JICA）が共同で実施しているSATREPS（サトレップス）プログラムのもと、日本とタイ国共同で研究を進め、プロジェクトの成果であるNAT2遺伝子検査や薬剤耐性結核菌遺伝子解析に基づいた治療方針の決定ならびにアウトブレイク調査のための結核菌の全ゲノムシークエンス解析がタイ国の結核対策ガイドラインに採用され、すでに保健省が提供する医療サービスとして開始されました。

プロジェクトホームページ

国立研究開発法人 科学技術振興機構 独立行政法人 国際協力機構

本研究に関する文献

Phelan J, Gomez-Gonzalez PJ, Andreu N, Omae Y, Toyo-Oka L, Yanai H, Miyahara R, Nedsuwan S, de Sessions PF, Campino S, Sallah N, Parkhill J, Smittipat N, Palittapongarnpim P, Mushiroda T, Kubo M, Tokunaga K, Mahasirimongkol S, Hibberd ML, and Clark TG: Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease. Nat. Commun. 14(1): 549, 2023.
Yuliwulandari R, Prayuni K, Razari I, Susilowati RW, Zulhamidah Y, Soedarsono S, Sofro ASM, and Tokunaga K. Genetic characterization of N-acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia. Pharmacogenomics 22(3): 157-163, 2021.
Tantivitayakul P, Juthayothin T, Ruangchai W, Smittipat N, Disratthakit A, Mahasirimongkol S, Tokunaga K, and Palittapongarnpim P. Identification and in silico functional prediction of lineage-specific SNPs distributed in DosR-related proteins and resuscitation-promoting factor proteins of Mycobacterium tuberculosis. Heliyon 6(12): e05744, 2020.
Soedarsono S, Amin M, Tokunaga K, Yuliwulandari R, Suameitria Dewi DNS, Mertaniasih NM. Association of disease severity with toll-like receptor polymorphisms in multidrug-resistant tuberculosis patients. Int J Mycobacteriol. 9(4): 380-390, 2020
Miyahara R, Smittipat N, Juthayothin T, Yanai H, Disratthakit A, Imsanguan W, Intralawan D, Nedsuwan S, Chaiyasirinroje B, Bupachat S, Tokunaga K, Mahasirimongkol S, and Palittapongarnpim P. Risk factors associated with large clusters of tuberculosis patients determined by whole-genome sequencing in a high-tuberculosis-burden country. Tuberculosis 125: 101991, 2020.
Tantivitayakul P, Ruangchai W, Juthayothin T, Smittipat N, Disratthakit A, Mahasirimongkol S, Viratyosin W, Tokunaga K, Palittapongarnpim P. Homoplastic single nucleotide polymorphisms contributed to phenotypic diversity in mycobacterium tuberculosis. Sci. Rep. 10(1): e8024, 2020.
Wichukchinda N, Pakdee J, Kunhapan P, Imunchot W, Toyo-Oka L, Tokunaga K, Mahasirimongkol S. Haplotype-specific PCR for NAT2 diplotyping. Hum Genome Var.7(1): e13, 2020.
Suvichapanich S, Wattanapokayakit S, Mushiroda T, Yanai H, Chuchottawon C, Kantima T, Suwankesawong W, Sonsupap C, Pannarunothai R, Tumpattanakul S, Bamrungram W, Chaiwong A, Mahasirimongkol S, Mameechai S, Panthong W, Klungtes N, Munsoo A, Chauychana U, Maneerat M, Fukunaga K, Omae Y, and Tokunaga K. Genome-wide association study confirming the association of NAT2 with susceptibility to anti-tuberculosis drug-Induced liver injury in Thai patients. Antimicrob Agents Chemother. 63(8): e02692-18, 2019.
Smittipat N, Miyahara R, Juthayothin T Billamas P, Dokladda K, Imsangaun W, Intralawan D, Rukseree K, Jaitrong S, Chaiyasirinrote, B, Wongyai J, Disratthakit A, Chaiprasert A, Nedsuwan S, Mahasirimongkol S, Toyo-oka L, Tokunaga K, Yamada N, Palittapongarnpim P, and Yanai H. Indo-Oceanic mycobacterium tuberculosis strains from Thailand associated with higher mortality. Int. J. Tuberc. Lung Dis. 23(9): 972-979, 2019.
Ajawatanawong P, Yanai H, Smittipat N, Disratthakit A, Yamada N, Miyahara R, Nedsuwan S, Imasanguan W, Kantipong P, Chaiyasirinroje B, Wongyai J, Plitphonganphim S, Tantivitayakul P, Phelan J, Parkhill J, Clark TG, Hibberd ML, Ruangchai W, Palittapongarnpim P, Juthayothin T, Thawornwattana Y, Viratyosin W, Tongsima S, Mahasirimongkol S, Tokunaga K, and Palittapongarnpim P. A novel Ancestral Beijing sublineage of Mycobacterium tuberculosis suggests the transition site to Modern Beijing sublineages. Sci. Rep. 9(1): 13718, 2019.
Yuliwulandari R, Prayuni K, Susilowati RW, Sofro ASM, Tokunaga K, and Shin JG. NAT2 slow acetylator is associated with anti-tuberculosis drug-induced liver injury severity in Indonesian population. Pharmacogenomics 20(18):1303-1311, 2019
Palittapongarnpim P, Ajawatanawong P, Viratyosin W, Smittipat N, Disratthakit A, Mahasirimongkol S, Yanai H, Yamada N, Nedsuwan S, Imasanguan W, Kantipong P, Chaiyasirinroje B, Wongyai J, Toyo-Oka L, Phelan J, Parkhill J, Clark TG, Hibberd ML, Ruengchai W, Palittapongarnpim P, Juthayothin T, Tongsima S, Tokunaga K. Evidence for Host-Bacterial Co-evolution via Genome Sequence Analysis of 480 Thai Mycobacterium tuberculosis Lineage 1 Isolates. Sci Rep. 8(1):11597, 2018
Suvichapanich S, Fukunaga K, Zahroh H, Mushiroda T, Mahasirimongkol S, Toyo-Oka L, Chaikledkaew U, Jittikoon J, Yuliwulandari R, Yanai H, Wattanapokayakit S, Tokunaga K. NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis. Pharmacogenet Genomics. 28(7):167-176, 2018
Omae Y, Toyo-oka L, Yanai H, Nedsuwan S, Wattanapokayakit S, Satproedprai N, Smittipat N, Palittapongarnpim P, Sawanpanyalert P, Inunchot W, Pasomsub E, Wichukchinda N, Mushiroda T, Kubo M, Tokunaga K, Mahasirimongkol S. Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis. J Hum Genet, 62(12):1015-1022, 2017
Toyo-Oka L, Mahasirimongkol S, Yanai H, Mushiroda T, Wattanapokayakit S, Wichukchinda N, Yamada N, Smittipat N, Juthayothin T, Palittapongarnpim P, Nedsuwan S, Kantipong P, Takahashi A, Kubo M, Sawanpanyalert P, Tokunaga K. Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis. HLA. 90(3):149-156, 2017
Ohigashi I, Ohte Y, Setoh K, Nakase H, Maekawa A, Kiyonari H, Hamazaki Y, Sekai M, Sudo T, Tabara Y, Sawai H, Omae Y, Yuliwulandari R, Tanaka Y, Mizokami M, Inoue H, Kasahara M, Minato N, Tokunaga K, Tanaka K, Matsuda F, Murata S, Takahama Y. A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production. JCI Insight. 18;2(10), 2017
Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, Rojanawiwat A, Denjanta S, Kantima T, Wongyai J, Suwankesawong W, Rungapiromnan W, Kidkeukarun R, Bamrungram W, Chaiwong A, Suvichapanich S, Mahasirimongkol S, Tokunaga K: NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients. Int J Tuberc Lung Dis. 2016 Oct;20(10):1364-1369.
Smittipat N, Juthayothin T, Billamas P, Jaitrong S, Rukseree K, Dokladda K, Chaiyasirinroje B, Disratthakit A, Chaiprasert A, Mahasirimongkol S, Yanai H, Yamada N, Tokunaga K, Palittapongarnpim P: Mutations in rrs, rpsL and gidB in streptomycin-resistant Mycobacterium tuberculosis isolates from Thailand. J Glob Antimicrob Resist. 2016 Mar;4:5-10.
Mushiroda T, Yanai H, Yoshiyama T, Sasaki Y, Okumura M, Ogata H, Tokunaga K: Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var. 2016 Jun 23;3:16014.
Nakauchi A, Wong JH, Mahasirimongkol S, Yanai H, Yuliwulandari R, Mabuchi A, Liu X, Mushiroda T, Wattanapokayakit S, Miyagawa T, Keicho N, Tokunaga K: Identification of ITPA on chromosome 20 as a susceptibility gene for young-onset tuberculosis. Hum Genome Var. 2016 Feb 4;3:15067.
Yuliwulandari R, Susilowati RW, Wicaksono BD, Viyati K, Prayuni K, Razari I, Kristin E, Syafrizal, Subagyo, Sri Diana E, Setiawati S, Ariyani A, Mahasirimongkol S, Yanai H, Mushiroda T, Tokunaga K: NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet. 2016 Jun;61(6):533-7.
Srilohasin P, Chaiprasert A, Tokunaga K, Nishida N, and Prammananan T. A novel DNA chip based on modified DigiTag2 assay for high throughput species identification and genotyping of Mycobacterium tuberculosis complex. J Clin Microbiol. 2014 Jun;52(6):1962-8
Mahasirimongkol S, Yanai H, Mushiroda T, Promphittayarat W, Wattanapokayakit S, Promjai J, Yuliwulandari R, Wichukchinda N, Yowang A, Yamada N, Kantipong P, Takahashi A, Kubo M, Sawanpanyalert P, Kamatani N, Nakamura Y, and Tokunaga K: Genomic-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis. J. Hum. Genet. 57(6): 363-367, 2012.
Kobayashi K, Yuliwulandari R, Yanai H, Naka I, Lien L, Hang NTL, Hijikata M, Keicho N, and Tokunaga K: Association study of TLR polymorphisms with development of tuberculosis. Tissue Antigens 79(3): 190-197, 2012
Hijikata M, Shojima J, Matsushita I, Tokunaga K, Ohashi J, Hang NT, Horie T, Sakurada S, Hoang NP, Thuong PH, Lien LT, and Keicho N: Association of IFNGR2 gene polymorphisms with pulmonary tuberculosis among the Vietnamese. Hum. Genet. 131(5): 675-682, 2012.
Kobayashi K, Yuliwulandari R, Yanai H, Lien LT, Hang NTL, Hijikata M, Keicho N, and Tokunaga K : Association between CD209 and development of tuberculosis in Indonesian and Vietnamese populations. Hum. Immunol. 72(9): 741-745, 2011.
Ridruechai C, Mahasirimongkol S, Phromjai J, Yanai H, Nishida N, Matsushita I, Ohashi J, Yamada N, Moolphate S, Summanapan S, Chuchottaworn C, Manosuthi W, Kantipong P, Kanitvittaya S, Sawanpanyalert P, Keicho N, Khusmith S, and Tokunaga K*: Association analysis of susceptibility candidate region on chromosome 5q31 for tuberculosis. Genes Immun. 11(5): 416-22, 2010.
Yuliwulandari R, Sachrowardi Q, Nakajima F, Kashiwase K, Hirayasu K, Mabuchi A, Salam A M, and Tokunaga K*: Association of HLA-A, -B, and -DRB1 with pulmonary tuberculosis in western Javanese Indonesia. Hum. Imunol. 71(7): 697-701, 2010.
Mahasirimongkol S, Yanai H, Nishida N, Ridruechai C, Matsushita I, Ohashi J, Summanapan S, Yamada N, Moolphate S, Chuchotaworn C, Chapraser A, Manosuthi W, Kantipong P, Kantiwaittaya S, Sura T, Khusmith S, Tokunaga K, Sawanpanyaleert P, and Keicho N*: Genome-wide SNP-based linkage analysis of tuberculosis in Thais. Genes Immun. 10(1): 77-83, 2009
Vollstedt S, Yuliwulandari R, Okamoto K, Lien LT, Kicho N, Rochani JT, Wikaningrum R, and Tokunaga K*: No evidence for association between the interferon regulatory factor 1(IRF1) gene and clinical tuberculosis. Tuberculosis 89(1): 71-6, 2009.