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

Research Project

Project/Area Number 15H05271
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section海外学術
Research Field Human genetics
Research InstitutionThe 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 *help
¥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.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (49 results)

All 2017 2016 2015 Other

All Int'l Joint Research (12 results) Journal Article (8 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 3 results) Presentation (27 results) (of which Int'l Joint Research: 18 results,  Invited: 10 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] St. Jude Children's Research Hospital/Massachusetts General Hospital(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Oxford University(英国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] タイ保健省医科学局/Mahidol University(タイ)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Yarsi University(インドネシア)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] St. Jude Children’s Research Hospital(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Oxford University(英国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] タイ保健省医科学局/Mahidol University(タイ)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Yarsi University(インドネシア)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] St. Jude Children's Research Hospital(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Oxford University(英国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] タイ保健省医科学局/マヒドン大学(タイ)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Yarsi University(インドネシア)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis2017

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis2017

    • 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

    • Related Report
      2017 Annual Research Report
    • 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 Drugs2017

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Overview of the BioBank Japan Project: Study design and profile2017

    • 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
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients2016

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients2016

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Identification of ITPA as a susceptibility gene to young-onset tuberculosis on Chromosome 202016

    • 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

    • Related Report
      2015 Annual Research Report
    • 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 tuberculosis2016

    • 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

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] NAT2 rapid acetylator showed significant association with mortality in HIV positive tuberculosis patients2017

    • 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
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Trend of Tuberculosis incidence since 1987, Chiang Rai, Thailand: Impact of HIV epidemic and medico-social determinants2017

    • 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
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Risk factor for tuberculosis incidence and mortality in people living with HIV, Chiang Rai, Thailand2017

    • 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
    • Related Report
      2016 Annual Research Report
    • 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 method2017

    • 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
    • Related Report
      2016 Annual Research Report
    • 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
    • Related Report
      2016 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] HLA as predominant genetic factors for autoimmune diseases, infectious diseases and adverse drug reactions2017

    • Author(s)
      Tokunaga K
    • Organizer
      The 17th International HLA & Immunogenetics Workshop, Asilomar, USA
    • Related Report
      2017 Annual Research Report
    • 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 risk2017

    • 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
    • Related Report
      2017 Annual Research Report
  • [Presentation] Gene expression signature as a potential treatment monitoring biomarker for active tuberculosis in Thailand2017

    • 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
    • Related Report
      2017 Annual Research Report
    • 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 Thailand2017

    • 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)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Monocyte/Lymphocyte Ratio predict the risk of Tuberculosis among HIV-infected population in Mae Chan, Thailand2017

    • 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)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Search for Genetic Predispositions to Complex Diseases2016

    • Author(s)
      Tokunaka K
    • Organizer
      2016 Taiwan-Japan Joint Conference on Genomic Studies
    • Place of Presentation
      Taipei, Taiwan
    • Year and Date
      2016-12-15
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Association analysis identified susceptible alleles to tuberculosis based on imputed HLA class I and II alleles2016

    • 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
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genomic approaches to tuberculosis and hepatitis B virus related diseases2016

    • 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
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] A Statistical Exploration of How Multiple Enhancers Affect Traits Jointly2016

    • 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
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of novel susceptibility region for Tuberculosis on Chromosome 5q31.12016

    • 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
    • Related Report
      2016 Annual Research Report
    • 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 patients2016

    • 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
    • Related Report
      2016 Annual Research Report
    • 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
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Revisiting HLA polymorphisms and disease associations2015

    • Author(s)
      K Tokunaga
    • Organizer
      Asia-Pacific Histocompatibility and Immunogenetics Association Conference 2015
    • Place of Presentation
      Bangkok、Thailand
    • Year and Date
      2015-10-10
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] HLA association analysis stratified by specific strains of M.tuberculosis identify susceptible HLA class II alleles to tuberculosis2015

    • 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
    • Related Report
      2015 Annual Research Report
    • 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 Response2015

    • 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
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Utilizing genetic and environmental information in public health2015

    • 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
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] New disease susceptibility loci identified by a multiple SNPs interaction search in GWAS2015

    • 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
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HLA association analysis and haplotype analysis identify susceptible alleles of HLA class II to tuberculosis2015

    • 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
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome-wide search for disease-related genes with special reference to HLA-disease associations – Towards clinical application2015

    • Author(s)
      K Tokunaga
    • Organizer
      Yarsi Genomic Medicine Conference 2015
    • Place of Presentation
      Jakarta, Indonesaia
    • Year and Date
      2015-05-07
    • Related Report
      2015 Annual Research Report
    • 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/

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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