Association of single-nucleotide polymorphisms in CCR6, TAGAP, and TNFAIP3 with rheumatoid arthritis in African Americans

Abstract

Objective: We previously reported an analysis of single-nucleotide polymorphisms (SNPs) in 3 validated European rheumatoid arthritis (RA) susceptibility loci, TAGAP, TNFAIP3, and CCR6, in African American patients with RA. Unexpectedly, the disease-associated alleles were different in African Americans from those in Europeans. In an effort to better define their contribution, we performed additional SNP genotyping in these genes.

Methods: Seven SNPs were genotyped in 446 African American patients with RA and in 733 African American control subjects. Differences in minor allele frequency between the RA cases and controls were analyzed after controlling for the global proportion of European admixture, and pairwise linkage disequilibrium (LD) was estimated among the SNPs.

Results: Three SNPs were significantly associated with RA: the TNFAIP3 rs719149 A allele (OR 1.22 [95% confidence interval (95% CI) 1.03-1.44], P = 0.02), the TAGAP rs1738074 G allele (OR 0.75 [95% CI 0.63-0.89, P = 0.0012), and the TAGAP rs4709267 G allele (OR 0.74 [95% CI 0.60-0.91], P = 0.004). Pairwise LD between the TAGAP SNPs was low (r(2) = 0.034). The haplotype containing minor alleles for both TAGAP SNPs was uncommon (4.5%). After conditional analysis of each TAGAP SNP, its counterpart remained significantly associated with RA (rs1738074 for rs4709267 P = 0.00001 and rs4709267 for rs1738074 P = 0.00005), suggesting independent effects.

Conclusion: SNPs in regulatory regions of TAGAP and an intronic SNP (TNFAIP3) are potential susceptibility loci in African Americans. Pairwise LD, haplotype analysis, and SNP conditioning analysis suggest that these 2 SNPs in TAGAP are independent susceptibility alleles. Additional fine-mapping of this gene and functional genomic studies of these SNPs should provide further insight into the role of these genes in RA.