In their published article, Giles et al. (1) explored functional consequences of rs17611 in the TRAF1-C5 region and propose a mechanism for its contribution to rheumatoid arthritis (RA) pathology, as this SNP would associate with RA. To substantiate the claim that the SNP associates with RA, the authors referred to the following studies: Refs. 2 and 3.
However, the data presented by Kurreeman et al. do not indicate a significant association (p = 0.19) in 544 subjects (Ref. 2, see Table I). In addition, haplotype block analyses of this risk locus shows that block 2 is significantly associated with RA, while block 3 (which includes rs17611) is not (Ref. 2, see Fig. 1). Similar data by Plenge et al. (3) across 3372 subjects support this lack of association. Recent genome-wide association studies data across 55,000 European subjects (4) provide accurate estimations of risk across hundreds of SNPs in this locus. Again, no signal of association for rs17611 has been demonstrated in the available published datasets originating from this study (Fig. 1), which also shows that rs17611 is in relatively low linkage disequilibrium (LD) with the lead SNP rs10985070 (r2 = 0.4). Moreover, independent secondary association signals were not observed in the TRAF1-C5 locus in a study by Eyre et al. (5), excluding the possibility that rs17611 could represent a second hit at this locus.
Regional association plot for the TRAF1-C5 region. The x-axis shows the chromosomal position of the all queried SNPs located on chromosome 9p33p34 over a region of 500 kb. The y-axis displays the –log10 (p value) of associations with RA. The p values were a result of analysis on the European population as part of the Okada et al. paper (4): 14,361 RA cases and 43,923 controls from 18 studies of Europeans descent. Pairwise LD values (r2) were calculated from individuals of the 1000 Genomes Project (CEU) relative to the highest associating SNP rs10985070 using SNAP (6). N.D., LD for SNP is not determined.
Regional association plot for the TRAF1-C5 region. The x-axis shows the chromosomal position of the all queried SNPs located on chromosome 9p33p34 over a region of 500 kb. The y-axis displays the –log10 (p value) of associations with RA. The p values were a result of analysis on the European population as part of the Okada et al. paper (4): 14,361 RA cases and 43,923 controls from 18 studies of Europeans descent. Pairwise LD values (r2) were calculated from individuals of the 1000 Genomes Project (CEU) relative to the highest associating SNP rs10985070 using SNAP (6). N.D., LD for SNP is not determined.
On the basis of the published genetic data, we believe caution should be taken in implicating the effects of rs17611 in relation to the immunological mechanism underlying the genetic risk of TRAF1-C5 to RA.
