Introduction : Recent progress of genetic studies in rheumatology JCR 2009 April 24, 2009 Tokyo, Japan IMS-UT Ryo Yamada

Genetic Epidemiology and GWAS Prevalence – RA ( ～ 1%)> Lupus( ～ 0.5%) >>> Other Rheumatic Autoimmune diseases – Ethnic Difference, Regional Difference Relatively even RA vs. Heterogeneous Lupus Family Studies, Twin Studies Family-based Studies: Sib-pair Linkage Studies Population-based Studies: Association Studies – High-throughput Technology -> GWAS

Genetic Component Wandstrat A. and Wakeland E. Nat Immunol 2(9) 802,2001

Sib- pairs LD- mapping Replicatio n GWAS

CD244 FCRL3 PADI4 SLC22A 4 CD4 0 PDCD1 SLEGE N TNFSF 4 Shared Epitope WTCCC PTPN2 2 TRAF1/C 5 STAT4 BANK 1 IRF5 FCGR3 A

HLA and autoimmunities

LD Mapping and Functional Explanation snp Markers detect association nearby. Functional origin snp Markers distributes unevenly and their extension varies. Allele-specific function is what and from where? LD mapping identify regions of association but the origin(s) and functional explanation have yet to be confirmed in other ways.

Central Dogma and DNA Variations and their functionality ＤＮ Ａ mRNA Peptide Transcription Translation Transcription initiation point Transcription termination point Splicing and mRNA maturation Translation initiation point Codon triplets Translation termination point Variations Post-translational peptide modifications Molecules

Sub-microscopic variants Structural variants Microscopic variants Human Genome Substitution SNP Insertion Deletion Repeat Inversion Transposition CNV ♂♀ SNP and other polymorphisms HLA- DRB1 HLA class I,II,III

European Japanese Susceptible allele PDCD1 MIF1CTLA4SLC22A4/A5 PTPN22TNFRSF1PADI4 Ethnic difference in allele frequency of associated markers

Ethnic diversity and regional difference PTPN22 risk allele Seminars in Immunology Volume 18, Issue 4Seminars in Immunology Volume 18, Issue 4, August 2006, Pages ～０％

Ethnic heterogeneity in genetic background M Jakobsson* et.al.(2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:

Japanese Population Structure, Based on SNP Genotypes from 7003 Individuals Compared to Other Ethnic Groups: Effects on Population-Based Association Studies Am. J.um. Genet. (2008) Yumi Yamaguchi-Kabata et al. Gross ethnic differenceRegional heterogeneity in Japan

Replication studies ～ PTPN22 ～ Rheumatology (1):49-56 Y. H. Lee1, Y. H. Rho1, S. J. Choi1, J. D. Ji1, G. G. Song1, S. K. Nath2–4 and J. B. Harley

Phenotypes Susceptibility to diseases themeselves Sub-classes of diseases – Clinical phenotype subclasses – Genetic subclasses – Pathologic subclasses and prognostic subclasses Response to treatments Image from The National Institute of Health II. Effects Anti-CCP anntibody

Lab of Functional Genomics U of Tokyo Mark Lathrop Yukinori Okada Lab for Autoimmune CGM, RIKEN Kazuhiko Yamamoto Akari Suzuki Yuta Kochi Kenichi Shimane Keiko Myozen Kyoko Kobayashi Kiyo Shimada Miyako Yamanaka Emi Kanno Yusuke Nakamura Kyoto Univ. Fumihiko Matsuda Chikashi Terao Koichiro Ohmura Tsuneyo Mimori Meiko Takahashi Hisako Imamura Katsura Hirosawa Akiko Yoshizumi Miki Kokubo Shoko Matsubara Collaboration National Hospital Org. Sagamihara Shigeto Tohma Toshihiro Matsui Kota Shimada Hiroshi Furukawa