Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in persons of European ancestry confer risk of rheumatoid arthritis in African Americans

Abstract

Objective: Large-scale genetic association studies have identified >20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA risk in an African American population.

Methods: Twenty-seven candidate single-nucleotide polymorphisms (SNPs) were genotyped in 556 autoantibody-positive African Americans with RA and 791 healthy African American control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were compared with previously published ORs for RA patients of European ancestry. We then calculated a composite genetic risk score (GRS) for each individual based on the sum of all risk alleles.

Results: Overlap of the ORs and 95% CIs between the European and African American populations was observed for 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, and TNFAIP3 rs6920220) demonstrated ORs in the opposite direction from those reported for RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African American patients relative to control subjects were enriched for the risk alleles validated in European RA patients (P = 0.00005).

Conclusion: The majority of RA risk alleles previously validated for RA patients of European ancestry showed similar ORs in our population of African Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel RA risk alleles in African Americans.

Figure 1. Scatter plot of the odds ratios of SNPs with replicated association in European populations on the ordinate and OR of the same SNPs tested in the African-American (A-A) population on the abscissa

Solid markers indicate OR that are consistent between populations (Table 2A); open markers are those SNPs in which the OR are inconsistent between populations (Table 2B). The two triangle markers are those SNPs (rs3087243, CTLA4 and rs3093023, CCR6) with statistically significant association with RA in this African-American sample. The diamond at the top of the figure is PTPN22, which has an OR=1.94 and OR=1.23 in European ancestry RA patients and African-American RA patients, respectively.

Figure 2. Cumulative distribution of the GRS scores between cases (red) and controls (blue)

The y axis, P (x <= X), is the cumulative probability that individual cases or controls have less than the given GRS score. The GRS score is defined here as the individual proportion of risk alleles carried for the 27 SNPs which have validated association with RA in populations of European ancestry. The mean is 0.43 for cases and 0.41 for controls.