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 Linkage Disequilibrium Mapping Chromosome 1p

Genes associated with multiple autoimmune diseases

RA or Crohn disease-associated SNPs in Ch5q31 Cytokine cluster

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, (2003)

The SNPs associated with RA, Crohn disease or Psoriatic arthritis RILSLC22A4SLC22A5IRF1 10kb Genes Exons SNPs RUNX1 binding site RA Crohn L503F Heat shock element- binding site Psoriatic Arthritis Tokuhiro, S. et al. Peltekova, V. D. et al. Barton, A. et al. Yamazaki, K et al.

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

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

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

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

Peptidyl citrullination by PADI4 Loss of ionic NH2+ of Arg residue Effects on intra- and inter- molecular interactions C=NH 2 + NH 2 CH 2 HCNH 3 + COO - NH C=O NH 2 CH 2 HCNH 3 + COO - NH ArginineCitrulline PADIs

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 )

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

Caucasian Japanese PDCD1 MIF1CTLA4SLC22A4/A5 PTPN22TNFRSF1PADI4 Susceptible allele Preliminary calculation with random-effect model

Acknowledgment 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