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Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

Authors
Maria I Danila, Vincent A Laufer, Richard J Reynolds, Qi Yan, Nianjun Liu, Peter K Gregersen, Annette Lee, Marlena Kern, Carl D Langefeld, Donna K Arnett, and S Louis Bridges, Jr.
Abstract
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 autoantibodypositive 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.
Volume
2017
Page Range
177-187
DOI
10.2119/molmed.2017.00081
Date Published
June 29, 2017
Article PDF
17_081_Danila.pdf3046 KB
Supplemental Data
17_081_Danila_Suppl.pdf1093 KB
Keywords
Danila, Laufer, Reynolds, Yan, Liu, Gregersen, Lee, Kern, Langefeld, Arnett, Bridges, rheumatoid arthritis, RA, African Americans, genetic data, risk loci, Immunochip array, IChip, trans-ethic mapping, histocompatibility complex, LD structure
Article Type
Research Article