関節リウマチ発症・進展機構の解明:疾患関連遺伝子間、遺伝子-環境間相互作用の解析

• Project/Area Number: 18791061
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: 猪狩 勝則 Tokyo Women's Medical University, 医学部, 助教 (80343557)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2007: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: 関節リウマチ / 相互作用 / 遺伝子

Research Abstract

研究計画に沿って、新たに報告された疾患関連遺伝子について本研究計画で使用する集団での追認試験を行った。各遣伝子上の責任遺伝子変異のジェノタイピングを、ABI PRISM 7900HT(アプライドバイオシステムズ社)およびGeneAmpPCR System 9700(同)を利用し、TaqMan法を用いて行った。タイピング後にχ二乗検定、ハプロタイプ解析などの遺伝統計解析によりRAとの関連を確認し、関連を認めたものや、認めなかったものがあった。このうちのいくつかについては論文化して研究報告を行っている。
HLA-DRB1はこれまで知られている中で最も強い疾患感受性を示し、疾患重症化とも強い関連を示すことが明らかになっている。日本人でも強い疾患感受性を示すことは示されていたが、今回初めて大規模な解析で日本人でも疾患重症化と関連することを示した。
MMP3は臨床的に疾患重症化との関連が確立されており、有望な疾患重症化遺伝子である。このプロモーターにある多型とMMP3血中濃度との関連を確認し、また疾患重症化との関連も示唆された。
STAT4は欧米の他施設研究による大規模なゲノムスキャンにより関連を認めた関節リウマチ感受性遺伝子である。当施設でのサンプルに加え、国内で他施設研究を組織し、日本人での関連も確認できたが、疾患重症化との関連は確認できなかった。MHC2TA、CTLA4、ITGAV、PDCD1も欧米で確認された疾患感受性遺伝子である。当施設でのサンプルを用いて解析を行い、関連を認めた。ただしいずれも疾患重症化との関連は確認できなかった。
HLA-DRB1、MMP3を中心とした遺伝子間相互作用、遺伝子一環境間相互作用の解析も行ったが、有意な関連は認めなかった。

Research Products

• [Journal Article] Lack of association between PADI4 and functional severity in Japanese rheumatoid arthritis patients. (2008)
  • Author(s): Nishimoto K, Ikari K, et. al.
  • Journal Title: Annals of the Rheumatic Diseases 67 Pages: 431-2
  • Peer Reviewed
• [Journal Article] CTLA-4 CT60 polymorphism is not an independent genetic risk marker of rheumatoid arthritis in Japanese. (2008)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Journal Title: Annals of the Rheumatic Diseases 67 Pages: 428-9
  • Peer Reviewed
• [Journal Article] Effect of matrix metalloproteinase-3 functional SNP on serum matrix metalloproteinase-3 level and outcome measures in Japanes RA patients. (2008)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Journal Title: Rheumatology (Oxford) 47 Pages: 41-4
  • Peer Reviewed
• [Journal Article] MHC2TA is associated with rheumatoid arthritis in Japanese patients (2007)
  • Author(s): Iikuni N, Ikari K, et. al.
  • Journal Title: Annals of the Rheumatic Diseases 66 Pages: 274-5
  • Peer Reviewed
• [Journal Article] ITGAV polymorphism and the disease susceptibility in a Japanese rheumatoid arthritis population. (2007)
  • Author(s): Iikuni N, Ikari K, et. al.
  • Journal Title: Arthritis Research and Therapy 9 Pages: 405-405
  • NAID: 120005521017
  • Peer Reviewed
• [Journal Article] A role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis. (2007)
  • Author(s): Iwamoto T. Ikari K, et. al.
  • Journal Title: FEBS Journal 274 Pages: 4904-12
  • Peer Reviewed
• [Journal Article] Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population. (2007)
  • Author(s): Iwamoto T, Ikari K, et. al.
  • Journal Title: Journal of Human Genetics 52 Pages: 557-60
  • NAID: 40015411017
  • Peer Reviewed
• [Journal Article] MHC2TA is associated with rheumatoid arthritis in Japanese patients (2007)
  • Author(s): Iikuni N, Ikari K, et al.
  • Journal Title: Annals of the Rheumatic Diseases 66 Pages: 274-275
• [Journal Article] Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis (2006)
  • Author(s): Ikari K, et al.
  • Journal Title: Annals of the Rheumatic Diseases 65 Pages: 671-673
• [Journal Article] Association between PADI4 and rheumatoid arthritis : a meta-analysis (2006)
  • Author(s): Iwamoto T, Ikari K, et al.
  • Journal Title: Rheumatology 45 Pages: 804-807
• [Journal Article] Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population (2006)
  • Author(s): Ikari K, et al.
  • Journal Title: Rheumatology 45 Pages: 1345-1348
• [Journal Article] Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese.
  • Author(s): Kobayashi S, Ikari K, et. al.
  • Journal Title: Arthritis and Rheumatism (in press)
  • Peer Reviewed
• [Journal Article] A polymorphism in Fcγ IIIA receptor coding gene is a possible genetic marker to predict primary response to infliximab in Japanese rheumatoid arthritis patients.
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Journal Title: Annals of the Rheumatic Diseases (in press)
  • Peer Reviewed
• [Journal Article] Association of the MSX2 gene polymorphisms with ankylosing spondylitisin Japanese.
  • Author(s): Furuici T, Ikari K, et. al.
  • Journal Title: Journal of Human Genetics (in press)
  • Peer Reviewed
• [Presentation] Effect of MMP-3 functional SNP on serum MMP-3 level and outcome measures in Japanese RA patients. (2008)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Organizer: Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: San Francisco, USA
• [Presentation] PDCD1 Gene Polymorphisms are not associated with Susceptibility or Severity of Rheumatoid Arthritis in Japanese. (2007)
  • Author(s): Iikuni N, Ikari K, et. al.
  • Organizer: Annual Scientific Meeting of the American College of Rheumatology
  • Place of Presentation: Boston, USA
• [Presentation] The Role of Aryl Hydrocarbon Receptor in RA. (2007)
  • Author(s): Kobayashi S, Ikari K, et. al.
  • Organizer: Annual Scientific Meeting of the American College of Rheumatology
  • Place of Presentation: Boston, USA
• [Presentation] Influence of a Matrix Metalloproteinase 3 Promoter Polymorphism to Serum Titer of MMP-3 in a Japanese Rheumatoid Arthritis Cohort. (2007)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Organizer: Annual Scientific Meeting of the American College of Rheumatology
  • Place of Presentation: Boston, USA
• [Presentation] FCGR3A genotypes influence response to tumor necrosis factor alpha inhibitors in patients with rheumatoid arthritis. (2007)
  • Author(s): Ikari K, et. al.
  • Organizer: Annual Meeting of American Society of Human Genetics
  • Place of Presentation: San Diego, USA
• [Presentation] HLA-DRB1 is associated with disease susceptibility and severity of rheumatoid arthritis in Japanese. (2007)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Organizer: Annual Meeting of American Society of Human Genetics
  • Place of Presentation: San Diego, USA
• [Presentation] MMP-28 regulates proteolytic activation of MT1-MMP. (2007)
  • Author(s): Nishimoto K, Ikari K, et. al.
  • Organizer: Combined Meeting, Orthopedic Reseach Societies
  • Place of Presentation: Honolulu, USA
• [Presentation] The role of TCDD and AhR in RA pathogenesis. (2007)
  • Author(s): Kobayashi S, Ikari K, et. al.
  • Organizer: Combined Meeting, Orthopedic Reseach Societies
  • Place of Presentation: Honolulu, USA
• [Presentation] MMP-3 promoter polymorphism is associated with total serum MMP-3levels, but not associated with radiographic joint damage in Japanese rheumatoid arthritis patients. (2007)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Organizer: Combined Meeting, Orthopedic Reseach Societies
  • Place of Presentation: Honolulu, USA
• [Presentation] Lack of Association between PADI4 and Disease Severity in Rheumatoid Arthritis Patients. (2007)
  • Author(s): Nishimoto K, Ikari K, et. al.
  • Organizer: Annual European Congress of Rheumatology
  • Place of Presentation: Barcelona, Spain
• [Presentation] Lack of Association between PDCD1 Gene Polymorphisms and Rheumatoid Arthritis in a Japanese Population. (2007)
  • Author(s): Iikuni N, Ikari K, et. al.
  • Organizer: Annual European Congress of Rheumatology
  • Place of Presentation: Barcelona, Spain
• [Presentation] MMP-3 is not Associated with Functional Severity in Japanese Rheumatoid Arthritis Patients. (2007)
  • Author(s): Tsukahara S, Ikari K, et. al.
  • Organizer: Annual European Congress of Rheumatology
  • Place of Presentation: Barcelona, Spain
• [Presentation] 関節リウマチにおける新規疾患感受性遺伝子の同定 (2007)
  • Author(s): 西本和正、猪狩勝則, 他
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 浜松市
• [Presentation] 日本人関節リウマチ患者におけるHLA-DRB1遺伝子座と疾患感受性および重症化との関連 (2007)
  • Author(s): 塚原聡、猪狩勝則, 他
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] 関節リウマチ疾患感受性遺伝子PADI4のメタ解析と疾患重症度との関連 (2007)
  • Author(s): 西本和正、猪狩勝則, 他
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] LRP5遺伝子多型と女性RA患者における新規骨折の関連:大規模前向き観察研究(I0RRA)を用いた解析より (2007)
  • Author(s): 古谷武文、猪狩勝則, 他
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] 関節リウマチ患者における生物学的製剤に対する治療反応性とFCGR3Aの遺伝子多型との関連の検討 (2007)
  • Author(s): 塚原聡、猪狩勝則, 他
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] 関節リウマチ患者のMMP3遺伝子と血清MMP3値、関節破壊との関連 (2007)
  • Author(s): 塚原聡、猪狩勝則, 他
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] 日本人関節リウマチ患者におけるCRP遺伝子多型と血清CRP値との関連にっいて (2007)
  • Author(s): 小林秀、猪狩勝則, 他
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 東京
• [Presentation] メタ解析によるPADI4遺伝子多型と関節リウマチとの疾患関連解析 (2007)
  • Author(s): 岩本卓士、猪狩勝則, 他
  • Organizer: 日本整形外科学会学術大会
  • Place of Presentation: 神戸
• [Presentation] LRP5遺伝子多型と女性RA患者における新規骨折の関連 (2007)
  • Author(s): 古谷武文、猪狩勝則, 他
  • Organizer: 日本リウマチ学会総会
  • Place of Presentation: 横浜
• [Presentation] 関節リウマチ疾患感受性遺伝子PADI4と疾患重症度との関連 (2007)
  • Author(s): 西本和正、猪狩勝則, 他
  • Organizer: 日本リウマチ学会総会
  • Place of Presentation: 横浜
• [Presentation] マトリックスメタロプロテアーゼ3遺伝子多型と関節リウマチ重症化との関連 (2007)
  • Author(s): 塚原聡、猪狩勝則, 他
  • Organizer: 日本リウマチ学会総会
  • Place of Presentation: 横浜