Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans
More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody-positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10−15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10−4 < p < 3.1 × 10−6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 — but no variants within the major histocompatibility complex — were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.
We thank the CLEAR investigators for recruiting participants with rheumatoid arthritis and healthy controls: Doyt Conn, MD (Grady Hospital and Emory University, Atlanta, Georgia); Beth Jonas, MD; Leigh Callahan, PhD (University of North Carolina, Chapel Hill); Edwin Smith, MD (Medical University of South Carolina, Charleston); Richard Brasington, MD (Washington University, St. Louis, Missouri); and Larry W Moreland, MD (University of Pittsburgh). We thank Drs. Robert Kimberly and Jeffrey Edberg for providing data on healthy controls from the Birmingham, Alabama, area. We would also like to thank Gleb Kichaev (David Geffen School of Medicine, University of California, Los Angeles) for helpful discussions regarding trans-ethnic fine mapping.
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