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SNP を用いた 関節リウマチ関連遺伝子解析の現況

SNP を用いた 関節リウマチ関連遺伝子解析の現況. 理化学研究所 遺伝子多型研究センター 関節リウマチ関連遺伝子研究チーム 山田　亮. Large Scale SNP-based Linkage Disequilibrium Mapping ホールゲノムアプローチ RIKEN( 日本 ) 連鎖解析・標的遺伝子領域アプローチ U. of Manchester (UK) NARAC(USA). Gene. SNP. Block. Inetr-block LD. No haplotypes. No htSNPs.

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SNP を用いた 関節リウマチ関連遺伝子解析の現況

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  1. SNPを用いた関節リウマチ関連遺伝子解析の現況SNPを用いた関節リウマチ関連遺伝子解析の現況 理化学研究所 遺伝子多型研究センター 関節リウマチ関連遺伝子研究チーム 山田　亮

  2. Large Scale SNP-based Linkage Disequilibrium Mapping ホールゲノムアプローチRIKEN(日本)連鎖解析・標的遺伝子領域アプローチU. of Manchester (UK)NARAC(USA)

  3. Gene SNP Block Inetr-block LD No haplotypes No htSNPs Linkage Disequilibrium Mapping Chromosome 1p

  4. Genes associated with multiple autoimmune diseases

  5. RA or Crohn disease-associated SNPs in Ch5q31 Cytokine cluster

  6. SLC22A4とRUNX1 • SLC22A4 • 有機カチオントランスポータ • 生理的機能は未知 • Crohn病, Asthma・アトピー関連遺伝領域(5q13)に存在 • RUNX1 • 血球系転写因子 • 白血病原因遺伝子 • 自己免疫疾患関連遺伝子か？ • SLE､乾癬とも関連 Tokuhiro S et al. Nat Genet 35, 341-348 (2003)

  7. 10kb RIL SLC22A4 SLC22A5 IRF1 Genes Exons Crohn Psoriatic Arthritis RA Yamazaki, K et al. SNPs Heat shock element-binding site RUNX1 binding site L503F Tokuhiro, S. et al. Barton, A. et al. Peltekova, V. D. et al. The SNPs associated with RA, Crohn disease or Psoriatic arthritis

  8. 3 genes with RUNX1 binding sequence SLE Prokunina, L. et al. Psoriasis RA Helms, C. et al. Tokuhiro, S. et al.

  9. RA, SLE and Psoriasis-associated SNPs disrupt RUNX1 binding motif

  10. Environmental Entry of Antigen Production of Antigen Genetic Body Response to Antigen Presentation of Antigen Recognition of Presented Antigen Immune System Transient Autoreaction Manifestation of phenotype Maintained Autoreaction Medical Encyclopedia From the Atlas of Renal PathologyAmerican Journal of Kidney Diseases, Volume 32, Issue 1

  11. PTPN22 • 1p13 • 110kDa 細胞質内tyrosine phosphatase • 機能性SNP （1858C->T, R620W) • Positive association • IDDM(Caucasian, Italian)Bottini N et al. • RA(Caucasian)Begovich AB et al. • SLE(Caucasian)Kyogoku, C. et al. • 多型自体が日本人には存在しない

  12. Arginine Citrulline NH2 NH2 C=NH2 + C=O NH NH CH2 CH2 CH2 CH2 CH2 CH2 PADIs HCNH3+ HCNH3+ COO- COO- Peptidyl citrullination by PADI4 Loss of ionic NH2+ of Arg residue Effects on intra- and inter- molecular interactions

  13. 関節リウマチ診断における、最も信頼できる自己抗体関節リウマチ診断における、最も信頼できる自己抗体 抗シトルリン化ペプチド抗体（抗CCP抗体)

  14. Replication study from Japan Japan 1: Suzuki et al. Japan 2: Kuwahara et al.

  15. Caucasian PDCD1 MIF1 CTLA4 SLC22A4/A5 PTPN22 TNFRSF1 PADI4 Preliminary calculation with random-effect model Susceptible allele Japanese

  16. Lab. Rheumatic Diseases Dr. K. Yamamoto Dr. A. Suzuki Dr. X.Chang Dr. Y. Kochi Mr. S. Tokuhiro Ms. R. Kawaida Ms. M. Mori Ms. K. Kobayashi Ms. M. Ohtake Ms. E. Kannno Ms. K. Komakine SRC, RIKEN Dr. A. Sekine Dr. T. Tsunoda Dr. Y. Nakamura Mr. H. Kawakami Mr. T. Kawaguchi Clinical Institutes Dr. T. Sawada And many other collaborators Acknowledgment

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