TRAF1 polymorphisms associated with rheumatoid arthritis susceptibility in Asians and in Caucasians

Abstract

Objective. Recent genome-wide association scans and replication studies of European populations have disclosed several single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA) susceptibility. The aim of this study was to evaluate the RA-associated loci by genotyping previously reported SNPs and additional tag SNPs in a Korean population.Methods. A total of 1,316 unrelated RA patients and 1,006 controls were genotyped for 12 SNPs identified in genome-wide scans and for 12 additional tag SNPs in IL2RB, OLIG3-TNFAIP3, PTPN22, and TRAF1-C5, and the findings were statistically compared.Results. None of the SNPs tested was associated with RA susceptibility, except rs7021206 in TRAF1 intron 3 (P ‫؍‬ 0.0032) and, among the SNPs previously reported, rs6457617 in HLA (P ‫؍‬ 4.6 ؋ 10 ؊35 ). The association of rs7021206 was positive in patients who were seropositive for rheumatoid factor (P ‫؍‬ 0.0051) or for anti-cyclic citrullinated peptide autoantibodies (P ‫؍‬ 0.0062). However, Korean patients were negative for the association of rs3761847 in the TRAF1-C5 intergenic region previously reported in Caucasians. Linkage disequilibrium between rs3761847 and rs7021206 was not as high in Koreans (r 2 ‫؍‬ 0.37) as in Caucasians (r 2 ‫؍‬ 0.67), which explains the lack of association of rs3761847 in Koreans. Accordingly, RA susceptibility was localized to an extended haplotype marked by rs7021206 rather than rs3761847, and SNPs highly correlated with rs7021206 (r 2 > 0.81) extended from rs1953126 in the PHF19-TRAF1 intergenic region to rs2900180 in the TRAF1-C5 intergenic region, spanning 66 kb.Conclusion. Our results demonstrate that within and around TRAF1, excluding PHF19 and C5, SNPs highly correlated with rs7021206, but not those correlated with rs3761847, are associated with RA in both Asians and Caucasians and are possibly correlated with causative variations.

Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis: a meta-analysis

“…Electronic and manual searches resulted in the identification of 30 studies, and 11 were selected for full-text review based on their titles and abstracts [9][10][11][12][13][14][15][16][17][18]27]. One study was excluded because it contained no extractable data [27].…”

“…One study was excluded because it contained no extractable data [27]. Thus, ten studies were considered in this meta-analysis [9][10][11][12][13][14][15][16][17][18], and comprised six European, two Asian, one African-American, and one Tunisian population (Table 1). Meta-analyses were conducted separately on the rs6920220, rs10499194, and rs2230926 polymorphisms.…”

“…Associations between TNFAIP3 polymorphisms and RA have been reported in different ethnic groups, but reported results are contradictory [9][10][11][12][13][14][15][16][17][18]. Typically, the allelic frequencies of genes often differ substantially in different ethnic groups, and thus ethnicity specific association studies are required to determine genetic associations in different populations [19][20][21].…”

Common variants at the promoter region of theAPOMconfer a risk of rheumatoid arthritis

“…Even within a similar ethnic group, the association of some candidate genetic markers to RA was differently reported. For example, polymorphisms in OLIG3 or TNFAIP3 genes were reported to be significantly associated with RA in Japanese (Kochi et al, 2010) but not in Korean population (Han et al, 2009). Recent meta-analysis of GWAS also suggested that only a small amount of the genetic component can be explained by the known RA risk alleles (Raychaudhuri et al, 2008;Stahl et al, 2010).…”

Pharmacogenetics of rheumatoid arthritis: Potential targets from susceptibility genes and present therapies

“…[87][88][89][90][91][92] Specifically, a study of 3962 RA patients and 3531 healthy controls demonstrated strong association (OR = 1.2; 95% CI: 1.1-1.3; P = 2.6 × 10 -6 ) with a variant (rs6920220) in an intergenic region of chromosome 6q23 region between oligodendrocyte linear transcription factor 3 (OLIG3) and TNF-α-induced protein 3 (TNFAIP3). 91 The validity of this study has been confirmed by a recent metaanalysis of seven studies investigating the association of the TNFAIP3-OLIG3 region with RA, which indicated a strong association of the variant rs6920220 (OR = 1.2, 95% CI: 1.2-1.3; P = 7.9 × 10 -17 ).…”