Introduction : Recent progress of genetic studies in rheumatologyJCR 2009April 24, 2009Tokyo, Japan

IMS-UTRyo Yamada

Genetic Epidemiologyand GWASPrevalenceRA (1%)> Lupus(0.5%) >>> Other Rheumatic Autoimmune diseasesEthnic Difference, Regional DifferenceRelatively even RA vs. Heterogeneous LupusFamily Studies, Twin StudiesFamily-based Studies: Sib-pair Linkage StudiesPopulation-based Studies: Association StudiesHigh-throughput Technology -> GWAS

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

GWAS

CD244FCRL3PADI4SLC22A4CD40PDCD1SLEGENTNFSF4Shared EpitopeWTCCCPTPN22TRAF1/C5STAT4BANK1IRF5FCGR3A

HLA and autoimmunities

LD Mapping and Functional ExplanationAllele-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 functionalitymRNAPeptideTranscriptionTranslationTranscription initiation pointTranscription termination pointSplicing and mRNA maturationTranslation initiation pointCodon tripletsTranslation termination pointPost-translational peptide modificationsMolecules

1010210310410510610710810910101Sub-microscopic variantsStructural variantsMicroscopic variantsHuman GenomeSubstitutionSNPInsertion DeletionRepeatInversionTranspositionCNVSNP and other polymorphismsHLA-DRB1HLA class I,II,III

EuropeanJapaneseSusceptible alleleEthnic difference in allele frequency of associated markers

Ethnic diversity and regional differencePTPN22 risk alleleSeminars in Immunology Volume 18, Issue 4, August 2006, Pages 214-223

Ethnic heterogeneity in genetic background M Jakobsson* et.al.(2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451: 998-1003.

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 studiesPTPN22Rheumatology 2007 46(1):49-56 Y. H. Lee1, Y. H. Rho1, S. J. Choi1, J. D. Ji1, G. G. Song1, S. K. Nath24 and J. B. Harley

PhenotypesSusceptibility to diseases themeselvesSub-classes of diseasesClinical phenotype subclassesGenetic subclassesPathologic subclasses and prognostic subclassesResponse to treatmentsImage from The National Institute of Health http://www.nlm.nih.gov/medlineplus/ency/imagepages/17134.htmII. EffectsAnti-CCP anntibody

Lab of Functional GenomicsIMS @ U of Tokyo Mark Lathrop Yukinori OkadaLab for Autoimmune Diseases @ CGM, RIKEN Kazuhiko Yamamoto Akari Suzuki Yuta Kochi Kenichi Shimane Keiko Myozen Kyoko Kobayashi Kiyo Shimada Miyako Yamanaka Emi Kanno Yusuke NakamuraCGM @ Kyoto Univ. Fumihiko Matsuda Chikashi Terao Koichiro Ohmura Tsuneyo Mimori Meiko Takahashi Hisako Imamura Katsura Hirosawa Akiko Yoshizumi Miki Kokubo Shoko MatsubaraCollaborationNational Hospital Org. SagamiharaShigeto TohmaToshihiro MatsuiKota ShimadaHiroshi Furukawa

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