Slide 1

Identification of rheumatoid arthritis-associated PADI4, SLC22A4/A5, FCRL3 & PTPN22 International Symposium on Inflammatory Diseases of Barrier Organs 3-4 June 2005, Kiel, Germany Ryo Yamada Center for Genomic Medicine Kyoto University Kyoto, Japan Slide 2 Genetics and Genetic Analysis of Rheumatoid Arthritis Twin and family studies Relative risk to monozygotic twin ( MZ ) 12~62 Relative risk to siblings ( sib ) 2~17 HLA locus explains 1/3-1/2 of total genetic components. There are multiple non-HLA genes. Multiple linkage studies Many candidate-approach studies Slide 3 Slide 4 Major findings from SNP-based studies PADI4 : RA Post-translational enzyme to produce targets of the most RA-specific autoantibodies. SLC22A4 /A5 : RA & Crohn Ergothioneine or carnitine transporter expressed in hematologic lineages. PTPN22 : T1DM, SLE, RA & AITD Lymphoid-specific intracellular phophatase FCRL3 : RA, SLR & AITD Fc receptor homolog on B-cell membrane Slide 5 Ca 2+ -dependent post-translational modification 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 Slide 6 K Arita M Sato et al. Nat Str & Mol Biol 2004 Ca 2+ -dependent post-translational modification Slide 7 Slide 8 PADI4 Citrullination Antigenicity Slide 9 Human and Mouse PADI Gene cluster Slide 10 Slide 11 Association Plots in the PADI Cluster -log 10 (P) PADI4 Slide 12 Enzyme substrate Slide 13 Hypothetical mechanism of RA-susceptible variant Slide 14 Following studies Case-control association studies UK (Barton, A. J., Worthington et al. 2004 Arthritis & Rheum) : Similar allele frequency No statistical significance Japanese (Kuwahara, M., Kamatani, N et al. 2004 ACR Poster) Allelic effect on expression Higher concentration of PADI4 in PBMC from individuals with more copies of RA-susceptible haplotype (Harney, S.M., Brown, M.A. et al. 2004 ACR Poster) Allelic effect on autoantibody-production Combinatorial effect on anti-CCP Ab production between HLA and PADI4 polymorphisms (Constantin, A., Cantagrel, A., et al. 2004 ACR Poster) Slide 15 Sugar transporter signature sequence motif N C 12 3 4 5 6 7 89 10 11 Nucleotide binding motif * * * * + + + + + SLC22A4(/A5) Slide 16 Slide 17 The SNPs associated with RA or Crohn disease RILSLC22A4SLC22A5IRF1 10kb Genes Exons SNPs RUNX1 binding site RA & Crohn Crohn L503F Heat shock element- binding site Psoriatic Arthritis Tokuhiro, S. et al. Peltekova, V. D. et al. Barton, A. et al. Japanese Caucasian Slide 18 SNP1 0.29 0.09 0.04 T, R620W) Positive association IDDM (Caucasian, Italian) Bottini N et al. RA (Caucasian) Begovich AB et al. SLE (Caucasian) Kyogoku, C. et al. No Tryptophan (W) allele in Japanese Slide 27 PTPN22 10kb Genes Exons SNPs PTPN22 Chromosome 1p13 ArgTrp J C A P value F ST P value F ST P value F ST SNP1 0.00 0.08 0.02