title: Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility.
abstract: Rheumatoid arthritis (RA) is an archetypal, common, complex autoimmune disease with both genetic and environmental contributions to disease aetiology. Two novel RA susceptibility loci have been reported from recent genome-wide and candidate gene association studies. We, therefore, investigated the evidence for association of the STAT4 and TRAF1/C5 loci with RA using imputed data from the Wellcome Trust Case Control Consortium (WTCCC). No evidence for association of variants mapping to the TRAF1/C5 gene was detected in the 1860 RA cases and 2930 control samples tested in that study. Variants mapping to the STAT4 gene did show evidence for association (rs7574865, P = 0.04). Given the association of the TRAF1/C5 locus in two previous large case-control series from populations of European descent and the evidence for association of the STAT4 locus in the WTCCC study, single nucleotide polymorphisms mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3000 cases with disease and >3000 controls and a combined analysis including the WTCCC data was undertaken. We confirm association of the STAT4 and the TRAF1/C5 loci with RA bringing to 5 the number of confirmed susceptibility loci. The effect sizes are less than those reported previously but are likely to be a more accurate reflection of the true effect size given the larger size of the cohort investigated in the current study.
authors.affiliation: Arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK. anne.barton@manchester.ac.uk
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Xiayi
authors.initials: X
authors.lastname: Ke
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.forename: Laura
authors.initials: L
authors.lastname: Gibbons
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Ioanna
authors.initials: I
authors.lastname: Marinou
authors.forename: Ann
authors.initials: A
authors.lastname: Morgan
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Sophia
authors.initials: S
authors.lastname: Steer
authors.forename: Lynne
authors.initials: L
authors.lastname: Hocking
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: Pille
authors.initials: P
authors.lastname: Harrison
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
mesh_terms: D000906:Antibodies / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor / Q000235:genetics*; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*
chemical_list: D000906:Antibodies; D010456:Peptides, Cyclic; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D047990:TNF Receptor-Associated Factor 1; C487763:cyclic citrullinated peptide