Kim Kwangwoo, Bang So-Young, Lee Hye-Soon, Cho Soo-Kyung, Choi Chan-Bum, Sung Yoon-Kyoung, Kim Tae-Hwan, Jun Jae-Bum, Yoo Dae Hyun, Kang Young Mo, Kim Seong-Kyu, Suh Chang-Hee, Shim Seung-Cheol, Lee Shin-Seok, Lee Jisoo, Chung Won Tae, Choe Jung-Yoon, Shin Hyoung Doo, Lee Jong-Young, Han Bok-Ghee, Nath Swapan K, Eyre Steve, Bowes John, Pappas Dimitrios A, Kremer Joel M, Gonzalez-Gay Miguel A, Rodriguez-Rodriguez Luis, Ärlestig Lisbeth, Okada Yukinori, Diogo Dorothée, Liao Katherine P, Karlson Elizabeth W, Raychaudhuri Soumya, Rantapää-Dahlqvist Solbritt, Martin Javier, Klareskog Lars, Padyukov Leonid, Gregersen Peter K, Worthington Jane, Greenberg Jeffrey D, Plenge Robert M, Bae Sang-Cheol
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
Ann Rheum Dis. 2015 Mar;74(3):e13. doi: 10.1136/annrheumdis-2013-204749. Epub 2014 Feb 14.
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.
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.
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.
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.
类风湿关节炎的遗传学研究已充分阐明其高度多基因病因及不同祖先之间的高度等位基因共享情况。最近，用于免疫疾病位点的高密度基因分型芯片Immunochip在欧洲血统个体中鉴定出14个新的类风湿关节炎风险位点。在此，我们旨在利用韩国特异性Immunochip数据鉴定新的类风湿关节炎风险位点。
我们使用Immunochip和全基因组关联研究（GWAS）芯片分析韩国类风湿关节炎病例对照样本，以寻找抗瓜氨酸化肽抗体阳性的类风湿关节炎新风险等位基因。为了提高检验效能，我们对韩国数据与先前发表的欧洲Immunochip和GWAS数据进行荟萃分析，总样本量为9299例韩国病例对照样本和45790例欧洲病例对照样本。
我们鉴定出8个新的类风湿关节炎易感位点（TNFSF4、LBH、EOMES、ETS1 - FLI1、COG6、RAD51B、UBASH3A和SYNGR1），这些位点达到全基因组显著性阈值（p<5×10⁻⁸），且在1q25/TNFSF4处有3个独立风险等位基因的证据。除TNFSF4位点（在韩国人中为单态性）外，其余7个新位点的风险等位基因与先前确定的类风湿关节炎风险位点的风险等位基因在不同祖先之间表现出较高的效应大小相关性。此外，我们通过对高密度基因分型单核苷酸多态性（SNP）进行跨种族比较，优化了代表潜在因果变异的SNP数量。
本研究证明了密集定位和跨祖先分析在鉴定潜在因果SNP方面的优势。此外，我们的研究结果支持T细胞在发病机制中的重要性以及不同自身免疫性疾病风险位点频繁重叠这一事实。
