Large Scale SNPbased Linkage Disequilibrium Mapping RIKEN U
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)
Linkage Disequilibrium Mapping Chromosome 1 p Gene SNP Block Inetr-block LD No haplotypes No ht. SNPs
Genes associated with multiple autoimmune diseases
RA or Crohn disease-associated SNPs in Ch 5 q 31 Cytokine cluster
The SNPs associated with RA, Crohn disease or Psoriatic arthritis 10 kb Genes RIL SLC 22 A 4 SLC 22 A 5 Exons RA Crohn Psoriatic Arthritis SNPs Heat shock element. RUNX 1 binding site L 503 F binding site Tokuhiro, S. et al. Peltekova, V. D. et al. Barton, A. et al. Yamazaki, K et al. IRF 1
3 genes with RUNX 1 binding sequence SLE Psoriasis RA Prokunina, L. et al. Helms, C. et al. Tokuhiro, S. et al.
RA, SLE and Psoriasis-associated SNPs disrupt RUNX 1 binding motif
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 Pathology American Journal of Kidney Diseases, Volume 32, Issue 1
PTPN 22 • 1 p 13 • 110 k. Da 細胞質内tyrosine phosphatase • 機能性SNP (1858 C->T, R 620 W) • 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 PADI 4 Arginine Citrulline NH 2 C=NH 2 + NH CH 2 HCNH 3+ COO- NH 2 C=O NH CH 2 PADIs CH 2 HCNH 3+ COO- Loss of ionic NH 2+ of Arg residue Effects on intra- and intermolecular interactions
Replication study from Japan 1: Suzuki et al. Japan 2: Kuwahara et al.
Caucasian PDCD 1 MIF 1 PTPN 22 CTLA 4 TNFRSF 1 Preliminary calculation with random-effect model Susceptible allele Japanese SLC 22 A 4/A 5 PADI 4
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
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