関節リウマチの遺伝的リスクスコア解析による関節破壊予測

• Project/Area Number: 15K10496
• 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: 桃原 茂樹 東京女子医科大学, 医学部, 非常勤講師 (00190984)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Discontinued (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ゲノム

Outline of Annual Research Achievements

本研究の目的はゲノムワイド関連解析（genome-wide association study: GWAS）のメタ解析によって同定された関節リウマチ（rheumatoid arthritis: RA）における101個の疾患感受性遺伝子が骨関節破壊の進行に影響を及ぼしているかどうか調査することであり、複数の遺伝子の組み合わせによる作用について遺伝的リスクスコア（genetic risk score: GRS）を利用した遺伝統計学的解析による評価を試みた。更に解析で特に有意となった遺伝子群によるGRSと臨床指標とを組み合わせることによってRA重症化におけるリスクを層別化する予測アルゴリズムを作成し、オーダーメイド医療に向けた基盤情報の構築を目指した。
1.国際共同研究によるGWASのメタ解析（Okada Y, et al. Nature 2014）によって同定された101個のRA疾患感受性遺伝子の内、RAの疾患重症化を規定する表現型（骨関節破壊の進行）と関連するSNPもしくは複数のSNPsの組み合わせの同定、および単一危険因子や従来の臨床的指標と比較した予測能の判定を行う。
2.同定された遺伝子については機能解析を行い、機能的遺伝子多型を同定する。
3.独立したサンプル群による結果の再現を検証する。
4.遺伝子多型情報に基づいた疾患重症化のリスク予測アルゴリズムを作成し、臨床応用につなげる。
研究代表者の異動に伴い、研究に十分な時間を割くことが困難となり、研究期間を全うすることなく終了することとなったが、上記1.および3.については解析を終え、HLA-DRB1などの骨破壊関連遺伝子群を同定できた。

Research Products

• [Journal Article] Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients with rheumatoid arthritis based on real-world data from the IORRA observational cohort study in Japan. (2017)
  • Author(s): Tanaka E, Inoue E, Yamaguchi R, Shimizu Y, Kobayashi A, Sugimoto N, Hoshi D, Shidara K, Sato E, Seto Y, Nakajima A, Momohara S, Taniguchi A, Yamanaka H.
  • Journal Title: Mod Rheumatol. Volume: - Issue: 2 Pages: 227-236
  • DOI: 10.1080/14397595.2016.1205799
  • Peer Reviewed
• [Journal Article] Continual Maintenance of Remission Defined by the ACR/EULAR Criteria in Daily Practice Leads to Better Functional Outcomes in Patients with Rheumatoid Arthritis. (2017)
  • Author(s): Shidara K, Nakajima A, Inoue E, Hoshi D, Sugimoto N, Seto Y, Tanaka E, Momohara S, Taniguchi A, Yamanaka H.
  • Journal Title: J Rheumatol. Volume: - Issue: 2 Pages: 147-153
  • DOI: 10.3899/jrheum.160395
  • Peer Reviewed
• [Journal Article] Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: interim analysis of a post-marketing surveillance study of 2679 patients in Japan. (2017)
  • Author(s): Mimori T, Harigai M, Atsumi T, Fujii T, Kuwana M, Matsuno H, Momohara S, Takei S, Tamura N, Takasaki Y, Ikeuchi S, Kushimoto S, Koike T.
  • Journal Title: Mod Rheumatol. Volume: - Issue: 5 Pages: 755-765
  • DOI: 10.1080/14397595.2016.1265695
  • Peer Reviewed
• [Journal Article] Effectiveness of tacrolimus in comparison with methotrexate or biologics in propensity score-matched patients with rheumatoid arthritis. (2016)
  • Author(s): Nakajima A, Inoue E, Taniguchi A, Momohara S, Yamanaka H.
  • Journal Title: Mod Rheumatol. Volume: 26 Issue: 6 Pages: 836-843
  • DOI: 10.3109/14397595.2016.1160969
  • Peer Reviewed
• [Journal Article] Tramadol hydrochloride/acetaminophen combination versus non-steroidal anti-inflammatory drug for the treatment of perioperative pain after total knee arthroplasty: A prospective, randomized, open-label clinical trial. (2016)
  • Author(s): Mochizuki T, Yano K, Ikari K, Hiroshima R, Takaoka H, Kawakami K, Koenuma N, Ishibashi M, Shirahata T, Momohara S.
  • Journal Title: J Orthop Sci. Volume: 21 Issue: 5 Pages: 625-629
  • DOI: 10.1016/j.jos.2016.07.011
  • Peer Reviewed
• [Journal Article] A twin study of rheumatoid arthritis in the Japanese population (2016)
  • Author(s): Terao, C., Ikari, K., Nakayamada, S., Takahashi, Y., Yamada, R., Ohmura, K., Hashimoto, M., Furu, M., Ito, H., Fujii, T., Yoshida, S., Saito, K., Taniguchi, A., Momohara, S., Yamanaka, H., Mimori, T., & Matsuda, F.
  • Journal Title: Modern Rheumatology Volume: 印刷中 Issue: 5 Pages: 685-689
  • DOI: 10.3109/14397595.2015.1135856
  • Peer Reviewed
• [Journal Article] Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis (2016)
  • Author(s): Okada Y, Suzuki A, Ikari K, Terao C, Kochi Y, Ohmura K, Higasa K, Akiyama M, Ashikawa K, Kanai M, Hirata J, Suita N, Teo YY, Xu H, Bae SC, Takahashi A, Momozawa Y, Matsuda K, Momohara S, Taniguchi A, Yamada R, Mimori T, Kubo M, Brown MA, Raychaudhuri S, Matsuda F, Yamanaka H, Kamatani Y, Yamamoto K
  • Journal Title: Am J Hum Genet Volume: 99 Issue: 2 Pages: 366-374
  • DOI: 10.1016/j.ajhg.2016.06.019
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impaired NFKBIE gene function decreases cellular uptake of methotrexate by down-regulating SLC19A1 expression in a human rheumatoid arthritis cell line (2016)
  • Author(s): Imamura H, YoshinaS, Ikari K, Miyazawa K, Momohara S, Mitani S
  • Journal Title: Mod Rheumatol Volume: - Issue: 4 Pages: 1-10
  • DOI: 10.3109/14397595.2015.1112481
  • NAID: 120007144512
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy of abatacept in Japanese patients with rheumatoid arthritis: 104 weeks radiographic and clinical results in clinical practice. (2016)
  • Author(s): Mochizuki T, Yano K, Ikari K, Hiroshima R, Takaoka H, Kawakami K, Koenuma N, Shirahata T, Momohara S.
  • Journal Title: Mod Rheumatol. Volume: 26 Issue: 4 Pages: 499-506
  • DOI: 10.3109/14397595.2015.1109578
  • Peer Reviewed
• [Journal Article] Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis. (2016)
  • Author(s): Kim K, Bang SY, Ikari K, Yoo DH, Cho SK, Choi CB, Sung YK, Kim TH, Jun JB, Kang YM, Suh CH, Shim SC, Lee SS, Lee J, Chung WT, Kim SK, Choe JY, Momohara S, Taniguchi A, Yamanaka H, Nath SK, Lee HS, Bae SC.
  • Journal Title: Sci Rep. Volume: - Issue: 1
  • DOI: 10.1038/srep27563
  • Peer Reviewed / Open Access
• [Journal Article] Association between serum vitamin D level and history of falls in elderly Japanese patients with rheumatoid arthritis. (2016)
  • Author(s): Ochi K, Furuya T, Ikari K, Taniguchi A, Yamanaka H, Momohara S.
  • Journal Title: Mod Rheumatol. Volume: 26 Issue: 3 Pages: 460-462
  • DOI: 10.3109/14397595.2015.1085487
  • Peer Reviewed