Genome-wide association study for rheumatoid arthritis using a large prospective cohort: a pilot study for personalized medicine.

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021023
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: MATSUDA Fumihiko 京都大学, 大学院・医学研究科, 教授 (50212220)
• Co-Investigator(Renkei-kenkyūsha): YAMANAKA Hisashi 東京女子医科大学, 医学部, 教授 (10166754)
• Project Period (FY): 2010 – 2011
• Project Status: Completed(Fiscal Year 2011)
• Budget Amount: ¥16,000,000 (Direct Cost : ¥16,000,000); Fiscal Year 2011 : ¥8,000,000 (Direct Cost : ¥8,000,000); Fiscal Year 2010 : ¥8,000,000 (Direct Cost : ¥8,000,000)
• Keywords: 関節リウマチ / 生物学的製剤 / 一塩基多型 / ゲノムワイド関連解析 / 薬剤感受性遺伝子

Research Abstract

We have established a national consortium for rheumatic disease study (GARNET Consortium) and accumulated more than 10,000 DNA samples of Japanese rheumatoid arthritis (RA) patients for genetic studies. We conducted a mata-analysis of genome-wide association (GWA) studies and newly identified 12 gene loci associated with RA in Japanese. We then investigated the biological role of myelin basic protein (MBP) gene, one of the above 12 genes, and found that autoantibodies against MBP were significantly increased in patients with RA beyond ethnicity, suggesting its usefulness as a diagnostic marker. We also found that multiple HLA-DRB1 alleles are associated with ACPA-negative rheumatoid arthritis in Japanese subjects. We have collected DNA samples of 299 RA patients treated with tocilizumab, biologic agent against interleukin 6 receptor, of which 120 DNA samples were subjected to the GWA study. Thirty-five candidate regions were identified, and the results are under confirmation with the other DNA samples.

Research Products

• [Journal Article] Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population (2012)
  • Author(s): Okada, Y., Terao, C., Ikari, K., Kochi, Y., Ohmura, K., Suzuki, A., Kawaguchi, T., Stahl, E.A., Kurreeman, F.A., Nishida, N., Ohmiya, H., Myouzen, K., Takahashi, M., Sawada, T., Nishioka, Y., Yukioka, M., Matsubara, T., Wakitani, S., Teshima, R., Tohma, S., Takasugi, K., Shimada, K., Murasawa, A., Honjo, S., Matsuo, K., Tanaka, H., Tajima, K., Suzuki, T., Iwamoto, T., Kawamura, Y., Tanii, H., Okazaki, Y., Sasaki, T., Gregersen, P.K., Padyukov, L., Worthington, J., Siminovitch, K.A., Lathrop, M., Taniguchi, A., Takahashi, A., Tokunaga, K., Kubo, M., Nakamura, Y., Kamatani, N., Mimori, T., Plenge, R.M., Yamanaka, H., Momohara, S., Yamada, R., Matsuda, F., and Yamamoto, K.
  • Journal Title: Nat. Genet. Volume : 44 Pages : 511-516
  • Peer Reviewed
• [Journal Article] Quantitative effect of HLA-DRB1 alleles to ACPA levels in Japanese rheumatoid arthritis: no strong genetic impact of shared epitope to ACPA levels after stratification of HLA-DRB1 (2012)
  • Author(s): Terao, C., Ikari, K., Ohmura, K., Suzuki, T., Iwamoto, T., Takasugi, K., Saji, H., Taniguchi, A., Momohara, S., Yamanaka, H., Matsuda, F., and Mimori, T.
  • Journal Title: Ann Rheum Dis. Volume : 71 Pages : 1095-1097
  • Peer Reviewed
• [Journal Article] A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations (2012)
  • Author(s): Meziani R., et al
  • Journal Title: Modern Rheumatology Volume : 22 Pages : 52-58
  • DOI: 10.1007/s10165-011-0467-y
  • Peer Reviewed
• [Journal Article] A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese (2012)
  • Journal Title: PLoS Genetics Volume : 8 Issue : 1 Pages : e1002455
  • Publisher: The Public Library of Science
  • DOI: 10.1371/journal.pgen.1002455
  • Year and Date: 2012-01-26
  • Peer Reviewed
• [Journal Article] The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population (2011)
  • Author(s): Terao, C., Yamada, R., Ohmura, K., Takahashi, M., Kawaguchi, T., Kochi, Y.; Human Disease Genomics Working Group; Rheumatoid Arthritis (RA) Clinical and Genetic Study Consortium, Okada, Y., Nakamura, Y., Yamamoto, K., Melchers, I., Lathrop, M., Mimori, T., and Matsuda, F.
  • Journal Title: Hum. Mol. Genet. Volume : 20 Pages : 2680-265
  • Peer Reviewed
• [Journal Article] Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis-a genome-wide study combined with immunological analyses (2011)
  • Author(s): Terao, C., Ohmura, K., Katayama, M., Takahashi, M., Kokubo, M,, Diop, G., Toda, Y., Yamamoto, N; Human Disease Genomics Working Group; Rheumatoid Arthritis (RA) Clinical and Genetic Study Consortium, Shinkura, R., Shimizu, M., Gut, I., Heath, S., Melchers, I., Manabe, T., Lathrop, M., Mimori, T., Yamada, R. and Matsuda F.
  • Journal Title: PLoS One Volume : 6
  • Peer Reviewed
• [Journal Article] A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects (2011)
  • Author(s): Terao, C., Ohmura, K., Kochi, Y., Ikari, K., Maruya, E., Katayama, M., Shimada, K., Murasawa, A., Honjo, S., Takasugi, K., Matsuo, K., Tajima, K., Suzuki, A., Yamamoto, K., Momohara, S., Yamanaka, H., Yamada, R., Saji, H., Matsuda, F. and Mimori, T.
  • Journal Title: Ann Rheum Dis Volume : 70 Pages : 2134-9
  • Peer Reviewed
• [Journal Article] The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population (2011)
  • Author(s): Terao C, et al
  • Journal Title: Human Molecular Genetics Volume : 20 Pages : 2680-2685
  • DOI: 10.1093/hmg/ddr161
  • Peer Reviewed
• [Journal Article] Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis-a genome-wide study combined with immunological analyses. (2011)
  • Journal Title: PloS one Volume : 6 Issue : 6
  • Publisher: Public Library of Science
  • DOI: 10.1371/journal.pone.0020457
  • PMID: 21673997
  • Peer Reviewed
• [Journal Article] Interferon-gamma release assay for diagnosing Mycobacterium tuberculosis infections in patients with systemic lupus erythematosus (2011)
  • Author(s): Takeda N., et al
  • Journal Title: Lupus Volume : 20 Pages : 792-800
  • DOI: 10.1177/0961203310397966
  • Peer Reviewed
• [Journal Article] A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects. (2011)
  • Journal Title: Annals of the rheumatic diseases Volume : 70 Issue : 12 Pages : 2134-2139
  • Publisher: BMJ Publishing Group Ltd & European League Against Rheumatism
  • DOI: 10.1136/annrheumdis-2011-200353
  • PMID: 21873689
  • Peer Reviewed
• [Journal Article] A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility (2010)
  • Author(s): Kochi, Y., Okada, Y., Suzuki, A., Ikari, K., Terao, C., Takahashi, A., Yamazaki, K., Hosono, N., Myouzen, K., Tsunoda, T., Kamatani, N., Furuichi, T., Ikegawa, S., Ohmura, K., Mimori, T., Matsuda, F., Iwamoto, T., Momohara, S., Yamanaka, H., Yamada, R., Kubo, M., Nakamura, Y., and Yamamoto, K.
  • Journal Title: Nat. Genet. Volume : 42 Pages : 515-519
  • Peer Reviewed
• [Journal Article] Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis (2010)
  • Author(s): Ohmura, K., Terao, C., Maruya, E., Katayama, M., Matoba, K., Shimada, K., Murasawa, A., Honjo, S., Takasugi, K., Tohma, S., Matsuo, K., Tajima, K., Yukawa, N., Kawabata, D., Nojima, T., Fujii, T., Yamada, R., Saji, H., Matsuda, F., and Mimori, T.
  • Journal Title: Rheumatol. Volume : 49 Pages : 2298-2304
  • Peer Reviewed
• [Journal Article] A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. (2010)
  • Author(s): 高地雄太
  • Journal Title: Nature Genetics Volume : 42 Pages : 515-9
  • Peer Reviewed
• [Journal Article] Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset : a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis. (2010)
  • Author(s): 大村浩一郎
  • Journal Title: Rheumatology (Oxford) Volume : 49 Pages : 2298-304
  • Peer Reviewed
• [Presentation] A large-scale association study identified multiple HLA-DRB1 alleles associated with anti-citrullinated peptide antibody negative rheumatoid arthritis in Japanese (2011)
  • Author(s): Terao Chikashi et al.
  • Organizer: Annual Congress of American College of Rheumatology
  • Place of Presentation: Chicago, USA
  • Year and Date: 2011-11-06
• [Presentation] A large-scale association study identihed multiple HLA-DRB1 alleles associated with anti-citrullinated peptide antibody negative rheumatoid arthritis in Japanese (2011)
  • Author(s): Chikashi Terao., et at
  • Organizer: アメリカリウマチ学会
  • Place of Presentation: McCormick Place Chicago USA
  • Year and Date: 2011-11-06
• [Presentation] 関節リウマチの病型と疾患感受性遺伝子、及びその機能解析 (2011)
  • Author(s): 寺尾知可史
  • Organizer: 日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル東京(招待講演)
  • Year and Date: 2011-09-15
• [Presentation] 抗CCP抗体陰性関節リウマチ関連HLA-DRB1アレルおよびディプロタイプの同定 (2011)
  • Author(s): 寺尾知可史, 他
  • Organizer: 日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル東京
  • Year and Date: 2011-09-15
• [Presentation] A haplotype of the human AIRE gene is associated with the risk for rheumatoid arthritis in Japanese population (2011)
  • Author(s): Terao Chikashi et al.
  • Organizer: EULAR Congress 2011
  • Place of Presentation: London, UK
  • Year and Date: 2011-05-27
• [Presentation] A haplotype of the human AIRE gene is associated with the risk for rheumatoid arthritis in Japanese population (2011)
  • Author(s): Chikashi Terao., et al
  • Organizer: ヨーロッパリウマチ学会
  • Place of Presentation: EXCEL London UK
  • Year and Date: 2011-05-27
• [Remarks]
  • URL: http://www.genome.med.kyoto-u.ac.jp/index.html
• [Patent(Industrial Property Rights)] 関節リウマチの新規遺伝因子としてのミエリン塩基性蛋白の利用 (2014)
  • Inventor(s): 松田文彦、三森経世、大村浩一郎、寺尾知可史
  • Industrial Property Rights Holder: 国立大学法人 京都大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-06-09
  • Application Year: 2014
  • Acquisition Date: 2017-04-21
  • Acquisition Year: 2017
• [Patent(Industrial Property Rights)] 関節リウマチの新規遺伝因子としてのミエリン塩基性蛋白の利用 (2011)
  • Inventor(s): 松田文彦, 三森経世, 大村浩一郎, 寺尾知可史
  • Industrial Property Rights Holder: 京都大学
  • Filing Date: 2011-04-01
  • Application Year: 2011
• [Patent(Industrial Property Rights)] 関節リウマチの新規遺伝因子としてのミェリン塩基性蛋白の利用 (2011)
  • Inventor(s): 松田文彦, 三森経世, 大村浩一郎, 寺尾知可史
  • Industrial Property Rights Holder: 京都大学
  • Filing Date: 2011-04-01
  • Application Year: 2011
• [Patent(Industrial Property Rights)] 関節リウマチの新規遺伝因子としてのミェリン塩基性蛋白の利用 (2011)
  • Inventor(s): 松田文彦, 三森経世, 大村浩一郎, 寺尾知可史
  • Industrial Property Rights Holder: 京都大学
  • Filing Date: 2011-04-01
  • Application Year: 2011
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