Genome-wide association study of drug response to methotrexate n rheumatoid arthritis patients

• Project/Area Number: 24592285
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: IKARI Katsunori 東京女子医科大学, 医学部, 准教授 (80343557)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 薬剤反応性遺伝子 / メトトレキセート / 関節リウマチ / メトトレキサート / 薬剤反応性 / 遺伝子

Outline of Final Research Achievements

First screening was done with the GWAS data from the other project (Human Omni Express). The study included 678 patients who had a history of MTX intake. Logistic regression analysis was used for statistical analysis. We identified three SNPs located near CCBE1, RCSD1 and EFR3A that were associated with drug response of methotrexate using genome-wide association study.

Research Products

• [Journal Article] TNFa but not IL-17 is critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcgRIIB-deficient mouse model. (2016)
  • Author(s): H.Nakamura, N.Iwamoto, T.Matsumoto, A.Kawakami
  • Journal Title: Mod. Rheumatol. Volume: 26(6) Pages: 837-841
  • Peer Reviewed
• [Journal Article] An association between the 74th amino acid position of HLA-DRB1 and ACPA levels of Japanese ACPA-positive RA. (2015)
  • Author(s): Terao C, Suzuki A, Ikari K, Kochi Y, Ohmura K, Katayama M, Nakabo S, Yamamoto N, Suzuki T, Iwamoto T, Yurugi K, Miura Y, Maekawa T, Takasugi K, Kubo M, Saji H,Taniguchi A, Momohara S, Yamamoto K, Yamanaka H, Mimori T, Matsuda F.
  • Journal Title: Arthritis Rheumatol. Volume: X
  • DOI: 10.1002/art.39133
  • Peer Reviewed
• [Journal Article] A main contribution of DRB1*04:05 among shared epitope and involvement of 57th DRB1 amino acid in association with joint destruction in ACPA(+) RA. (2015)
  • Author(s): Terao C, Yano K, Ikari K, Furu M, Yamakawa N, Yoshida S, Hashimoto M, Ito H,Fujii T, Ohmura K, Yurugi K, Miura Y, Maekawa T, Taniguchi A, Momohara S,Yamanaka H, Mimori T, Matsuda F.
  • Journal Title: Arthritis Rheumatol. Volume: X
  • DOI: 10.1002/art.39105
  • Peer Reviewed
• [Journal Article] Risk factors for established vertebral fractures in Japanese patients with rheumatoid arthritis: Results from a large prospective observational cohort study. (2015)
  • Author(s): Ishida O, Furuya T, Inoue E, Ochi K, Ikari K, Taniguchi A, Yamanaka H, Momohara S.
  • Journal Title: Mod Rheumatol. Volume: X
  • Peer Reviewed
• [Journal Article] Validity and responsiveness of a self-administered foot evaluation questionnaire in rheumatoid arthritis. (2015)
  • Author(s): Yano K, Ikari K, Ochi K, Ishida O, Sakuma Y, Yoshida S, Koyama T, Koenuma N, Momohara S.
  • Journal Title: Mod Rheumatol. Volume: X
  • Peer Reviewed
• [Journal Article] Ten-year incidences of self-reported non-vertebral fractures in Japanese patients with rheumatoid arthritis: discrepancy between disease activity control and the incidence of non-vertebral fracture. (2015)
  • Author(s): Ochi K, Inoue E, Furuya T, Ikari K, Toyama Y, Taniguchi A, Yamanaka H, Momohara S.
  • Journal Title: Osteoporos Int. Volume: 26 Pages: 961-8
  • DOI: 10.1007/s00198-014-2911-2
  • Peer Reviewed
• [Journal Article] Response to ‘Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regardless of anti-cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis: a case control study’ (2014)
  • Author(s): Ikari K, Yano K, Yoshida S, Taniguchi A, Yamanaka H, Momohara S.
  • Journal Title: Arthritis Res Ther. Volume: 16 Pages: 422-422
  • DOI: 10.1186/s13075-014-0422-3
  • Peer Reviewed / Open Access
• [Journal Article] An Osteoprotegerin Gene Polymorphism Is Associated with an Increased Risk of Hip Fracture in Japanese Patients with Rheumatoid Arthritis: Results from the IORRA Observational Cohort Study. (2014)
  • Author(s): Yoshida S, Ikari K, Furuya T, Toyama Y, Taniguchi A, Yamanaka H, Momohara S.
  • Journal Title: PLoS One. Volume: 9
  • DOI: 10.1371/journal.pone.0104587
  • Peer Reviewed / Open Access
• [Journal Article] Attrition rupture of ulnar nerve in an elbow of a patient with rheumatoid arthritis. (2014)
  • Author(s): Ochi K, Ikari K, Momohara S.
  • Journal Title: J Rheumatol. Volume: 41 Pages: 2085-2085
  • DOI: 10.3899/jrheum.140555
  • Peer Reviewed
• [Journal Article] Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population. (2014)
  • Author(s): Terao C, Ohmura K, Ikari K, Kawaguchi T, Takahashi M, Setoh K, Nakayama T,Kosugi S, Sekine A, Tabara Y, Taniguchi A, Momohara S, Yamanaka H, Yamada R,Matsuda F, Mimori T; Nagahama Study Group
  • Journal Title: Arthritis Care Res Volume: 66 Pages: 1818-1827
  • DOI: 10.1002/acr.22385
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recent trends in orthopedic surgery aiming to improve quality of life for those with rheumatoid arthritis: data from a large observational cohort. (2014)
  • Author(s): Momohara S, Inoue E, Ikari K, Ochi K, Ishida O, Yano K, Sakuma Y, Yoshida S, Koyama T, Koenuma N, Taniguchi A, Yamanaka H.
  • Journal Title: J Rheumatol. Volume: 41 Pages: 862-6
  • DOI: 10.3899/jrheum.131018
  • Peer Reviewed
• [Journal Article] Genetics of rheumatoid arthritis contributes to biology and drug discovery (2014)
  • Author(s): Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, （省略）, GARNET consortium, （以下省略）.
  • Journal Title: Nature Volume: 506 Pages: 376-381
  • DOI: 10.1038/nature12873
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lack of association between IL-15 genetic variants and progression of joint destruction in Japanese patients with rheumatoid arthritis (2014)
  • Author(s): Yoshida, S. Ikari, K. Yano, K. Toyama, Y. Taniguchi, A. Yamanaka, H. Momohara, S.
  • Journal Title: Ann Rheum Dis Volume: online
  • DOI: 10.1136/annrheumdis-2013-203921
  • Peer Reviewed
• [Journal Article] PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population. (2013)
  • Author(s): Terao C, Ohmura K, Kawaguchi Y, Nishimoto T, Kawasaki A, Takehara K, Furukawa H, Kochi Y, Ota Y, Ikari K, Sato S, Tohma S, Yamada R, Yamamoto K, Kubo M, Yamanaka H, Kuwana M, Tsuchiya N, Matsuda F, Mimori T
  • Journal Title: Arthritis Rheum. Volume: 65 Pages: 472-480
  • DOI: 10.1002/art.37777
  • Peer Reviewed
• [Journal Article] Non-synonymous variant (Gly307Ser) in CD226 is associated with susce ptibility in Japanese rheumatoid arthritis patients (2013)
  • Author(s): Suzuki, T. Momohara, S., et al.
  • Journal Title: Modern rheumatology Volume: 23 Pages: 200-2
  • DOI: 10.1007/s10165-012-0609-x
  • Peer Reviewed
• [Journal Article] A genome-wide sib-pair linkage analysis of ossification of the posterior longitudinal ligament of the spine (2013)
  • Author(s): Tatsuki Karasugi
  • Journal Title: J Bone Miner Metab Volume: 31(2) Pages: 136-143
  • DOI: 10.1007/s00774-012-0404-y
  • Peer Reviewed
• [Journal Article] ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese. (2013)
  • Author(s): Terao, C. Momohara, S., et al.
  • Journal Title: PLoS One Volume: 7
  • DOI: 10.1371/journal.pone.0040067
  • 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*09:01 (2012)
  • Author(s): Terao C, Ikari K, et al
  • Journal Title: Ann Rheum Dis Volume: (e-pub) Pages: 1095-1097
  • DOI: 10.1136/annrheumdis-2011-200907
  • Peer Reviewed
• [Journal Article] Meta-analysis of genome-wide association studies identifies multiple novel loci associated with rheumatoid arthritis in the Japanese population. (2012)
  • Author(s): Okada Y, Terao C, Ikari K, et al
  • Journal Title: Nat. Genet. Volume: (e-pub) Pages: 511-516
  • DOI: 10.1038/ng.2231
  • Peer Reviewed
• [Journal Article] Functional Variants in NFKBIE and RTKN2 Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese. (2012)
  • Author(s): Myouzen K, Kochi Y, Okada Y, Terao C, Suzuki A et al.
  • Journal Title: PLoS Genet. Volume: 8
  • DOI: 10.1371/journal.pgen.1002949
  • Peer Reviewed
• [Remarks] 東京女子医科大学膠原病リウマチ痛風センター
  • URL: http://www.twmu.ac.jp/IOR/