Identification of human genetic factors associated with tuberculosis and associated diseases through the meta-analysis and new statistical approaches

• Project/Area Number: 15H05271
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 海外学術
• Research Field: Human genetics
• Research Institution: The University of Tokyo
• Principal Investigator: Tokunaga Katsushi 東京大学, 大学院医学系研究科(医学部), 教授 (40163977)
• Co-Investigator(Kenkyū-buntansha): 莚田 泰誠 国立研究開発法人理化学研究所, その他, 研究員 (40392146) ; 野内 英樹 東京大学, 大学院医学系研究科(医学部), 客員研究員 (60437845) ; 大前 陽輔 東京大学, 大学院医学系研究科(医学部), 特任助教 (70722552)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 人類遺伝学 / ゲノム医科学 / 薬理遺伝学 / 結核 / 関連遺伝子 / 国際共同研究 / タイ / インドネシア / ゲノム / 感染症 / 遺伝子 / 遺伝統計 / 医療・福祉 / 結核症 / 国際メタ解析 / 国際コンソーシアム / アジア

Outline of Final Research Achievements

We have set up the Asian network to study human genetics factors associated with tuberculosis with common protocol. NAT2 slow acetylator status is confirmed as a risk factor of anti-tuberculosis drug-induced liver injury (ATDILI) in Thailand, Japan, and Indonesia. We conducted the first meta-analysis of NAT2 genotypes and risk of ATDILI and demonstrated that NAT2 ultra-slow acetylator status will have the significant effect on the increased risk of ATDILI, which has not been clear in the country-based analyses due to the small sample size. In addition, we have developed new statistical approach, logic regression, and long multigene haplotype analysis and proved their utility by our GWAS (genome-wide association study) data.

Research Products

• [Int'l Joint Research] St. Jude Children's Research Hospital/Massachusetts General Hospital(米国)
• [Int'l Joint Research] Oxford University(英国)
• [Int'l Joint Research] タイ保健省医科学局/Mahidol University(タイ)
• [Int'l Joint Research] Yarsi University(インドネシア)
• [Int'l Joint Research] St. Jude Children’s Research Hospital(米国)
• [Int'l Joint Research] Oxford University(英国)
• [Int'l Joint Research] タイ保健省医科学局/Mahidol University(タイ)
• [Int'l Joint Research] Yarsi University(インドネシア)
• [Int'l Joint Research] St. Jude Children's Research Hospital(米国)
• [Int'l Joint Research] Oxford University(英国)
• [Int'l Joint Research] タイ保健省医科学局/マヒドン大学(タイ)
• [Int'l Joint Research] Yarsi University(インドネシア)
• [Journal Article] Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis (2017)
  • Author(s): 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
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 6 Pages: 1015-1022
  • DOI: 10.1038/jhg.2017.8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis (2017)
  • Author(s): 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
  • Journal Title: HLA Volume: 90 Issue: 3 Pages: 149-156
  • DOI: 10.1111/tan.13070
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs (2017)
  • Author(s): Petros Z, Lee MT, Takahashi A, Zhang Y, Yimer G, Habtewold A, Schuppe-Koistinen I, Mushiroda T, Makonnen E, Kubo M, Aklillu E
  • Journal Title: OMICS Volume: 21 Issue: 4 Pages: 207-216
  • DOI: 10.1089/omi.2017.0019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Overview of the BioBank Japan Project: Study design and profile (2017)
  • Author(s): Nagai A, Hirata M, Kamatani Y, Muto K, Matsuda K, Kiyohara Y, Ninomiya T, Tamakoshi A, Yamagata Z, Mushiroda T, Murakami Y, Yuji K, Furukawa Y, Zembutsu H, Tanaka T, Ohnishi Y, Nakamura Y; BioBank Japan Cooperative Hospital Group., Kubo M
  • Journal Title: Journal of Epidemiology Volume: 27 Issue: Supplement_III Pages: S2-S8
  • DOI: 10.1016/j.je.2016.12.005
  • NAID: 130006832562
  • ISSN: 0917-5040, 1349-9092
  • Peer Reviewed / Open Access
• [Journal Article] NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients (2016)
  • Author(s): 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
  • Journal Title: International Journal of Tuberculosis and Lung Disease Volume: 10 Issue: 10 Pages: 1364-1369
  • DOI: 10.5588/ijtld.15.0310
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients (2016)
  • Author(s): Mushiroda T, Yanai H, Yoshiyama T, Sasaki Y, Okumura M, Ogata H, Tokunaga K
  • Journal Title: Human Genome Variation Volume: 3 Issue: 1 Pages: 16014-16014
  • DOI: 10.1038/hgv.2016.14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of ITPA as a susceptibility gene to young-onset tuberculosis on Chromosome 20 (2016)
  • Author(s): Nakauchi A, Wong JH, Mahasirimongkol S, Yanai H, Yuliwulandari R, Mabuchi A, Liu X, Mushiroda T, Wattanapokayakit S, Miyagawa T, Keicho N, Tokunaga K
  • Journal Title: Human Genome Variation Volume: 3 Issue: 1 Pages: 15067-15067
  • DOI: 10.1038/hgv.2015.67
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis (2016)
  • Author(s): 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
  • Journal Title: Journal of Human Genetics Volume: 61 Issue: 6 Pages: 533-537
  • DOI: 10.1038/jhg.2016.10
  • NAID: 40020857081
  • Peer Reviewed / Int'l Joint Research
• [Presentation] NAT2 rapid acetylator showed significant association with mortality in HIV positive tuberculosis patients (2017)
  • Author(s): Toyo-oka L, Mahasirimongkol S, Yanai1 H, Mushiroda T, Wichukchinda N, Yamada N, Nedsuwan S, Smittipat N, Disratthakit A, Imsanguan W, Kantipong P, Kubo M, Sawanpanyalert P, Tokunaga K.
  • Organizer: 6thConference of International Union Against Tuberculosis and Lung Disease, Asia Pacific Region (APRC2017)
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] Trend of Tuberculosis incidence since 1987, Chiang Rai, Thailand: Impact of HIV epidemic and medico-social determinants (2017)
  • Author(s): Nedsuwan S, Yamada N, Yanai H, Mahasirimongkol S, Wongyai J, Sayanpanyalert P, Yoshiyama T, Yamada N
  • Organizer: 6thConference of International Union Against Tuberculosis and Lung Disease, Asia Pacific Region (APRC2017)
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] Risk factor for tuberculosis incidence and mortality in people living with HIV, Chiang Rai, Thailand (2017)
  • Author(s): Piyaworawong S, Tsuchiya N, Miyahara R, Prechamat P, Kriengwatanapong P, Wongyai J, Bupachat S, Yanai H, Summanapan S, Mahasirimongkol S, Yamada N
  • Organizer: 6thConference of International Union Against Tuberculosis and Lung Disease, Asia Pacific Region (APRC2017)
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] Simultaneous quantification of first line anti-tuberculosis drugs in human plasma by development and validation of liquid chromatography tandem mass spectrometry method (2017)
  • Author(s): Mukmued P, Rojanawiwat A, Mahasirimongkol S,Buachum J, Sripaoraya K, Fukunaga K, Nosoongnoen W, Jittikoon J, Tokunaga K,Mushiroda T
  • Organizer: 6thConference of International Union Against Tuberculosis and Lung Disease, Asia Pacific Region (APRC2017)
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] 感染症とヒトの遺伝要因-肝炎と結核を例として (2017)
  • Author(s): 徳永勝士
  • Organizer: 国立感染症研究所学友会共催シンポジウム
  • Place of Presentation: 国立感染症研究所ハンセン病センター（東京都、東村山市）
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] ：感染症におけるヒトゲノム・病原体ゲノム解析: シンポジウム「ゲノム医科学の新展開」 (2017)
  • Author(s): 徳永勝士
  • Organizer: 生命科学系学会合同年次大会
  • Invited
• [Presentation] Meta-analysis of NAT2 Genotypes and the Risk for Anti-tuberculosis Induced Liver Injury (ATDILI) (2017)
  • Author(s): Suvichapanich S, Zarah H, Mushiroda T, Mahasirimongkol S, Toyo-oka L, Chaikledkaew U, Jittikoon J, Yuliwulandari R, Yanai H, Wattanapokayakit S, Tokunaga K
  • Organizer: The 15th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology 2017 (IATDMCT 2017)
  • Int'l Joint Research
• [Presentation] 免疫関連疾患、特に感染症のヒト遺伝要因 (2017)
  • Author(s): 徳永勝士
  • Organizer: Advanced Seminar Series on Microbiology and Immunology、大阪大学微生物病研究所
  • Invited
• [Presentation] HLA as predominant genetic factors for autoimmune diseases, infectious diseases and adverse drug reactions (2017)
  • Author(s): Tokunaga K
  • Organizer: The 17th International HLA & Immunogenetics Workshop, Asilomar, USA
  • Int'l Joint Research / Invited
• [Presentation] 複数遺伝子ハプロタイプの発見と自己免疫疾患リスクとの相関Long multigene haplotypes: their discovery, specificity to populations, and associations with autoimmune disease risk (2017)
  • Author(s): Yasui Y, Moon W, Im C, Nakamura M, Tokunaga K
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] Gene expression signature as a potential treatment monitoring biomarker for active tuberculosis in Thailand (2017)
  • Author(s): Miyahara R, Satproedprai N, Wichukchinda N, Yanai H, Toyo-oka L, Tokunaga K, Mahasirimongkol S
  • Organizer: the 67th Annual Meeting of The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] The association between the ratio of monocytes to lymphocytes and incidence of tuberculosis among antiretroviral treatment-naive HIV-infected adults in Lampang, northern Thailand (2017)
  • Author(s): Tsuchiya N, Wichukchinda N, Mahasirimongkol S, Rojanawiwat A, Naranbhai V, Yanai H, Tokunaga K, Ariyoshi K, Pathipvanich P, Sawanpanyalert P
  • Organizer: The 21st International Epidemiological Association (IEA) World Congress of Epidemiology (WCE2017)
  • Int'l Joint Research
• [Presentation] Monocyte/Lymphocyte Ratio predict the risk of Tuberculosis among HIV-infected population in Mae Chan, Thailand (2017)
  • Author(s): Miyahara R, Piyaworawong S, Tsuchiya N, Prechamat P, Kriengwatanapong P, Wongyai J, Bupachat S, Yamada N, Summanapan S, Mahasirimongko S, Yanai H
  • Organizer: The 21st International Epidemiological Association (IEA) World Congress of Epidemiology (WCE2017)
  • Int'l Joint Research
• [Presentation] Search for Genetic Predispositions to Complex Diseases (2016)
  • Author(s): Tokunaka K
  • Organizer: 2016 Taiwan-Japan Joint Conference on Genomic Studies
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2016-12-15
  • Invited
• [Presentation] Association analysis identified susceptible alleles to tuberculosis based on imputed HLA class I and II alleles (2016)
  • Author(s): Toyo-oka L, Mahasirimongkol S, Yanai H, Khor SS, Mushiroda T, Wichukchinda N, Wattanapokayakit S, Yamada N, Smittipat N, Juthayothin T, Palittapongarnpim P, Nedsuwan S, Kantipong P, Takahashi A, Kubo M, Sawanpanyalert P, Tokunaga K
  • Organizer: the 66th Annual Meeting of The American Society of Human Genetics(ASHG)
  • Place of Presentation: Vancouver Convention Center, Vancouver, BC, Canada
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Genomic approaches to tuberculosis and hepatitis B virus related diseases (2016)
  • Author(s): Tokunaga K, Mahasirimongkol S, Mizokami M
  • Organizer: International Seminar: Global Strategy to Combat Emerging Infectious Diseases in Borderless Era
  • Place of Presentation: Surabaya, Indonesia
  • Year and Date: 2016-08-08
  • Invited
• [Presentation] A Statistical Exploration of How Multiple Enhancers Affect Traits Jointly (2016)
  • Author(s): Yasui Y, Rampersaud E, Kang G, Hankins J, Estepp J, Wang S, Feng R, Palmer L, Wang Z, Yanai H, Robison L, Zhang J, Wu G, Tokunaga K, Weiss MJ
  • Organizer: 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館(京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Identification of novel susceptibility region for Tuberculosis on Chromosome 5q31.1 (2016)
  • Author(s): Wong JH, Nakauchi A, Mahasirimongkol S, Yanai1 H, Mabuchi A, Liu X, Mushiroda T, Miyagawa T, Keicho N, Tokunaga K
  • Organizer: 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館(京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Trans-ethnic Study of N-acetyltransferase 2 diplotypes in anti-tuberculosis drug-induced liver injury across Thai, Japanese, and Indonesian patients (2016)
  • Author(s): Suvichapanich S, Yuliwulandari R, Mushiroda T, Yanai H, Wattanapokayakit S, Mahasirimongkol S, Tokunaga K
  • Organizer: 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館(京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Pathogen lineage based analysis of host genetic risk factor in young onset tuberculosis. (2016)
  • Author(s): Omae Y, Mahasirimongkol S, Toyo-oka L, Yanai H, Nedsuwan S, Wattanapokayakit S, Smittipat N, Paliittapongarnpim P, Sawanpanyalert P, Wichukchinda N, Pasomsub E, Mushiroda T, Kubo M, Tokunaga K
  • Organizer: 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館(京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Revisiting HLA polymorphisms and disease associations (2015)
  • Author(s): K Tokunaga
  • Organizer: Asia-Pacific Histocompatibility and Immunogenetics Association Conference 2015
  • Place of Presentation: Bangkok、Thailand
  • Year and Date: 2015-10-10
  • Int'l Joint Research / Invited
• [Presentation] HLA association analysis stratified by specific strains of M.tuberculosis identify susceptible HLA class II alleles to tuberculosis (2015)
  • Author(s): Toyo-oka L, Mahasirimongkol S, Yanai H, Mushiroda T, Wattanapokayaki S, Wichukchinda N, Yamada N, Smittipat N, Nedsuwan S, Kantipong P, Takahashi A, Kubo M, Sawanpanyalert P, Tokunaga K
  • Organizer: Asia-Pacific Histocompatibility and Immunogenetics Association Conference
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-10-10
  • Int'l Joint Research
• [Presentation] ゲノム多様性、疾患感受性と薬剤応答性 Genome Diversity, Disease Susceptibility and Drug Response (2015)
  • Author(s): 徳永勝士
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル(東京都新宿区）
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] Utilizing genetic and environmental information in public health (2015)
  • Author(s): Surakameth Mahasirimongkol
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル(東京都新宿区）
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] New disease susceptibility loci identified by a multiple SNPs interaction search in GWAS (2015)
  • Author(s): Yasui Y, Sharafeldin N, Liu Q, Jabbari S, Wang L, Franco-Villalobos C, Mahasirimongkol S, Yanai H, Tokunaga K
  • Organizer: the 65th Annual Meeting of The American Society of Human Genetics(ASHG)
  • Place of Presentation: Baltimore、USA
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] HLA association analysis and haplotype analysis identify susceptible alleles of HLA class II to tuberculosis (2015)
  • Author(s): Toyo-oka L, Mahasirimongkol S, Yanai H, Mushiroda T, Wattanapokayakit S, Wichukchinda N, Yamada N, Smittipat N, Nedsuwan S, Kantipong P, Takahashi A, Kubo M, Sawanpanyalert P, Tokunaga K.
  • Organizer: the 65th Annual Meeting of The American Society of Human Genetics(ASHG)
  • Place of Presentation: Baltimore USA
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] Genome-wide search for disease-related genes with special reference to HLA-disease associations – Towards clinical application (2015)
  • Author(s): K Tokunaga
  • Organizer: Yarsi Genomic Medicine Conference 2015
  • Place of Presentation: Jakarta, Indonesaia
  • Year and Date: 2015-05-07
  • Invited
• [Remarks] 東京大学大学院医学系研究科人類遺伝教室
  • URL: http://www.humgenet.m.u-tokyo.ac.jp/
• [Patent(Industrial Property Rights)] 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 (2017)
  • Inventor(s): 東京大学、理化学研究所、タイ保健省医科学局
  • Industrial Property Rights Holder: 東京大学、理化学研究所、タイ保健省医科学局
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-150296
  • Filing Date: 2017