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High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

AbstractOBJECTIVE:
A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data.
METHODS:
We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples.
RESULTS:
We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.
CONCLUSIONS:
This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
AuthorsKwangwoo Kim, So-Young Bang, Hye-Soon Lee, Soo-Kyung Cho, Chan-Bum Choi, Yoon-Kyoung Sung, Tae-Hwan Kim, Jae-Bum Jun, Dae Hyun Yoo, Young Mo Kang, Seong-Kyu Kim, Chang-Hee Suh, Seung-Cheol Shim, Shin-Seok Lee, Jisoo Lee, Won Tae Chung, Jung-Yoon Choe, Hyoung Doo Shin, Jong-Young Lee, Bok-Ghee Han, Swapan K Nath, Steve Eyre, John Bowes, Dimitrios A Pappas, Joel M Kremer, Miguel A Gonzalez-Gay, Luis Rodriguez-Rodriguez, Lisbeth Ärlestig, Yukinori Okada, Dorothée Diogo, Katherine P Liao, Elizabeth W Karlson, Soumya Raychaudhuri, Solbritt Rantapää-Dahlqvist, Javier Martin, Lars Klareskog, Leonid Padyukov, Peter K Gregersen, Jane Worthington, Jeffrey D Greenberg, Robert M Plenge, Sang-Cheol Bae
JournalAnnals of the rheumatic diseases (Ann Rheum Dis) Vol. 74 Issue 3 Pg. e13 (Mar 2015) ISSN: 1468-2060 [Electronic] England
PMID24532676 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightPublished by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Topics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Arthritis, Rheumatoid (genetics)
  • Asian People (genetics)
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Republic of Korea (ethnology)
  • White People (genetics)
  • Young Adult

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