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1.  Association of Single Nucleotide Polymorphisms (SNPs) in CCR6, TAGAP and TNFAIP3 with Rheumatoid Arthritis in African Americans 
Arthritis and Rheumatism  2012;64(5):1355-1358.
Objective
We previously reported an analysis of single nucleotide polymorphisms (SNPs) in three validated European rheumatoid arthritis (RA) susceptibility loci, TAGAP, TNFAIP3, and CCR6 in African-Americans with RA. Unexpectedly, the disease-associated alleles were different in African-Americans than 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 Americans with RA and 733 African American controls. Differences in minor allele frequency between cases and controls were analyzed after controlling for global proportion of European admixture, and pairwise linkage disequilibrium (LD) was estimated among the SNPs.
Results
Three SNPs were significantly associated with RA: TNFAIP3 rs719149 A allele (OR (95% CI) 1.22 (1.03–1.44) (p =0.02); TAGAP rs1738074 G allele OR 0.75 (0.63–0.89), (p =0.0012); and TAGAP rs4709267 G allele 0.74 (0.60–0.91), (p =0.004). Pairwise LD between the TAGAP SNPs was low (R2=0.034). The haplotype containing minor alleles for both TAGAP SNPs was uncommon (4.5%). After conditional analysis on each TAGAP SNP, its counterpart remained significantly associated with RA (rs1738074 for rs4709267 p=0.00001; rs4709267 for rs1738074 p=0.00005), suggesting independent effects.
Conclusions
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 two SNPs in TAGAP are independent susceptibility alleles. Additional fine mapping of this gene and functional genomic studies of these SNPs should provide additional insight into the role of these genes in RA.
doi:10.1002/art.33464
PMCID: PMC3299842  PMID: 22127930
4.  An African Ancestry-Specific Allele of CTLA4 Confers Protection against Rheumatoid Arthritis in African Americans 
PLoS Genetics  2009;5(3):e1000424.
Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.
Author Summary
Rheumatoid arthritis (RA) is a systemic autoimmune condition affecting the synovial membranes of diarthrodial joints. The etiology of RA is unclear but is thought to result from an environmental trigger in the context of genetic predisposition. We report that a single nucleotide polymorphism (SNP) (rs231778) in CTLA4, which encodes a negative regulator of T cell activation, is associated (p = 2.4×10−28) with protection from developing RA among African Americans. rs231778 is only polymorphic in populations of African ancestry. Protective alleles such as this one may contribute to the purported lower prevalence of RA in African Americans. Our finding appears to be independent from confounding by linkage with the HLA-DRB1 shared epitope or by genetic admixture. Furthermore, we did not replicate associations of CTLA4 SNPs with RA or other autoimmune diseases previously reported in Asians and Caucasians, such as rs3087243 (+60C/T) and rs231775 (+49A/G). The associations of different SNPs with RA susceptibility specific to different populations highlight the importance of CTLA4 in the pathogenesis of RA and demonstrate the ethnic-specific genetic background that contributes to its susceptibility.
doi:10.1371/journal.pgen.1000424
PMCID: PMC2652071  PMID: 19300490

Results 1-4 (4)