Most Common SNPs Associated with Rheumatoid Arthritis in Subjects of European Ancestry Confer Risk of Rheumatoid Arthritis in African-Americans

Rheumatoid arthritis (RA) is a phenotypically heterogeneous, systemic autoimmune disease characterized by chronic destructive inflammation in synovial joints. The disease can be subdivided into two groups (autoantibody-positive or autoantibody-negative) according to the presence or absence of either rheumatoid factor (RF) or autoantibodies to cyclic-citrullinated peptide (CCP). Genetic and environmental risk factors and their interaction are also known contributors to RA pathogenesis (1). Advances in human genetics have led to a dramatic increase in the number of disease risk alleles identified in persons of European ancestry with RA, with at least 20 common risk alleles discovered to date (2;3). However, because the vast majority of the large-scale genetic association studies have been conducted in autoantibody-positive persons of European ancestry, the question about whether these alleles are associated with RA risk in other ethnic groups remains unaddressed. We sought to study the association of these previously identified RA risk loci in a large group of well-characterized African-Americans with RA. Specifically, we hypothesized that many of the risk loci identified in populations of European ancestry will also demonstrate risk for RA in African Americans. Most RA risk alleles outside of the MHC region have moderate effect sizes and have thus required large sample sizes for identification and replication. We anticipated that it would be difficult to demonstrate strong statistical support for individual risk alleles in our African American population of 556 autoantibody-positive RA cases and 791 healthy controls. To address this limitation we used two methodological approaches. We first tested whether individual risk allele OR are consistent (have overlapping confidence intervals) or inconsistent (non-overlapping confidence intervals) between the European and African-American populations. As a second step we derived an aggregate genetic risk score (GRS) in our population of African-American RA and controls and analyzed for differences in the composite effect of all European risk alleles with RA risk (4).