Investigation of association between the TRAF family genes and RA susceptibility.
OBJECTIVE
The tumour necrosis factor (TNF) receptor-associated factor (TRAF) family is important in activating multiple inflammatory and immune related processes induced by cytokines such as TNFalpha and interleukin-1. These genes therefore represent strong candidate susceptibility factors for rheumatoid arthritis (RA). A study was undertaken to investigate the association between single nucleotide polymorphisms (SNPs) spanning six TRAF genes and RA in a British population.


METHODS
Twenty-three haplotype tagging (ht) SNPs and 26 random SNPs spanning the six TRAF genes were initially tested for association in a cohort of 351 unrelated patients with RA and 368 controls. Any SNPs demonstrating an association were genotyped in further samples. Sequenom MassARRAY technology 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 transcription factor binding site, demonstrated a significant association across the entire cohort of 1273 cases with RA compared with 2463 healthy controls (OR for minor T allele 1.2 (95% CI 1.06 to 1.36), p = 0.005). The association was stronger in the subgroup carrying at least one copy of the shared epitope alleles (OR 1.43 (95% CI 1.18 to 1.73), p = 0.0003).


CONCLUSIONS
These findings provide evidence for the association of an 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.
Potter
Catherine
C
Arthritis Research Campaign Epidemiology Unit, Stopford Building, University of Manchester, Manchester M13 9PT, UK.
Eyre
Stephen
S
Cope
Andrew
A
Worthington
Jane
J
Barton
Anne
A
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics; D053449:TNF Receptor-Associated Factor 4 / Q000235:genetics; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics*
D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D053449:TNF Receptor-Associated Factor 4; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins