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Genetic Influences on Susceptibility to Rheumatoid Arthritis in African-Americans

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Laufer VA1, Tiwari HK2, Reynolds RJ1, Danila MI1, Wang J2, Edberg JC1, Kimberly RP1, Kottyan LC3, Harley JB4,5, Mikuls TR6, Gregersen PK7, Absher DM8, Langefeld CD9, Arnett DK10, Louis Bridges S Jr1. Hum Mol Genet. 2018 Nov 13. doi: 10.1093/hmg/ddy395. [Epub ahead of print]


Author information 1 Department of Medicine,University of Alabama at Birmingham,Birmingham,AL,USA,35294. 2 Department of Biostatistics,University of Alabama at Birmingham,Birmingham,AL,USA,35294. 3 Center for Autoimmune Genetics and Etiology, Cincinnati Children's Hospital Medical Center,Cincinnati,OH,USA45229. 4 Center for Autoimmune Genetics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 45229. 5 US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA 45220. 6 VA Nebraska-Western Iowa Health Care System and the Department of Internal Medicine,University of Nebraska Medical Center,Omaha,NE,USA,68198. 7 The Robert S. Boas Center for Genomics and Human Genetics,Feinstein Institute for Medical Research,North Short LIJ Health System,Manhasset,NY,USA,11030. 8 Hudson Alpha Institute for Biotechnology,Huntsville,AL,USA,35806. 9 Department of Biostatistical Sciences,Wake Forest University School of Medicine,Winston-Salem,NC,27101. 10 University of Kentucky College of Public Health,Lexington,KY,40508.

Abstract Large meta-analyses of RA susceptibility in European and East Asian populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans are absent. To address this disparity, we performed an analysis of 916 African-American RA patients and 1392 controls, and aggregated our data with genotyping data from >100,000 European and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to African-Americans: GPC5 and RBFOX1 (pAA < 5 x 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in Europeans. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of African-American data to those of European and East Asian descent enabled identification of 7 novel high confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include African-Americans, identified several new RA risk loci, and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.