To date, the majority of GWAS and subsequent meta-analyses of GWAS data in RA have focused on subjects of European and East Asian ancestry. It has become clear from these and other large scale genetic studies of complex diseases such as RA that genetic risk loci can differ among these different ethnic groups (18
). There is a paucity of data from well-characterized, large groups of African-Americans with RA. In this study we sought to test the hypothesis that RA risk alleles validated in populations of European ancestry would also be associated with RA in African-Americans. The power to test individual risk alleles in our African American sample is limited compared to studies in European RA. The results of this study, however, demonstrated that cumulatively (via the GRS analysis), risk alleles for RA in Europeans also confer risk for African Americans. Therefore, we conclude that the two populations are best characterized as genetically homogeneous with respect to validated risk alleles for RA.
We found that the ORs between European and African-American populations were consistent for 24 of 27 European RA risk loci. One interpretation of this finding is that the genetic etiology of RA risk in the two populations is very similar. However, only one European RA risk allele achieved statistically significant association with risk of RA in the African-American population (CTLA4 rs3087243). Although the CLEAR cohort is the largest group of African-American RA patients currently available for analysis, we had limited power to detect genetic associations. This limited power, as shown in , can be attributed to the small effect size of many individual risk alleles and the low frequency of some of the risk alleles in the African-American population. The limited power to detect association signals also affected our ability to demonstrate between population inconsistencies in OR. For example, the low frequency PTNP22 SNP rs2476601 (MAF = 0.01) showed the largest between-population difference (), with OR of 1.23 in African-Americans and 1.94 in Europeans. However, due to the large confidence interval limit on the African-American OR, we were unable conclude that these OR were different between populations ().
We observed differences in direction of OR between European and African American populations for three loci (CCR6
rs394581, and TNFAIP3
rs6920220). There are at least three explanations for these differences. First, inconsistent ORs might be due to weakened correlations between tag SNPs and the causal allele (not yet identified) with actual risk with RA. It is known from the International Haplotype Mapping Project (HapMap) that LD structure between European and African American populations may be different for common SNPs in any given locus. Such an effect may be particularly striking if the causal allele is rare in the population (e.g., frequency <5%)(28
). The second possible explanation is that these differences may be explained by genetic heterogeneity; the European risk allele may operate differently in its effect on RA risk for African-Americans. Such population specific differences may reflect gene by gene or gene by environmental interactions. The third possible explanation is that the inconsistency may simply be due to chance, given the number of hypotheses tested. Further investigation of these alleles among individuals of African ancestry is needed in explore these possibilities.
Although we had limited statistical power because of our small sample size, when the SNP risk alleles are viewed together in the GRS analysis, there is evidence that the European risk alleles are also risk alleles in the African American population. The GRS was found to be significantly different between RA cases and controls, even after excluding the CTLA4 SNP with the largest effect size. However this approach indicates that even though most of the individual markers were not statistically associated with RA in African-Americans, they may contribute to a panel of alleles that collectively confer risk.
Future studies of large, well-characterized cohorts of African-American RA patients and controls are needed to definitively determine whether the European RA risk alleles are associated with RA risk in African-Americans. Large scale GWAS in African-American RA patients are also needed in order to explore novel risk alleles among this genetically admixed ethnic group. We believe that detailed genetic studies of African-Americans with RA will lead to important insights into the pathogenesis of this disease.