Abstract

Objective: The TNF receptor-associated factor (TRAF) family are important in activating multiple inflammatory and immune related processes induced by cytokines such as TNFα and IL-1. Thus, these genes represent strong candidate susceptibility factors for rheumatoid arthritis (RA). The present study was undertaken to investigate association between single nucleotide polymorphisms spanning 6 TRAF genes and RA in a British population.

Methods: Twenty three haplotype-tagging (ht) and 26 random SNPs spanning the 6 TRAF genes were initially tested for association in a cohort of 351 unrelated patients with RA and 368 controls. Any SNPs demonstrating association were genotyped in further samples. Sequenom MassARRAY® technology (Cambridge, UK) was preferentially used for genotyping. Both single point and haplotypic analyses were performed.

Results Forty-four SNPs were successfully genotyped and conformed to Hardy Weinberg expectation. A single SNP, rs7514863, mapping upstream of the TRAF5 gene and affecting a putative TFBS demonstrated a significant association across the entire cohort of 1,273 cases with RA compared to 2,463 healthy controls (OR for minor T allele = 1.2 (95% CI=1.06- 1.36), p= 0.005). The association was stronger in the subgroup carrying at least 1 copy of the shared epitope alleles (OR=1.43 (95% CI=1.18-1.73), p=0.0003).

Conclusion: These findings provide evidence for the association of a SNP upstream of a strong candidate RA susceptibility gene, TRAF5, in a large cohort of patients and controls. Further association and functional studies are required to investigate the role of this variant, or one in linkage disequilibrium with it, in RA disease causation.