Human Molecular Genetics Advance Access originally published online on April 22, 2008
Human Molecular Genetics 2008 17(15):2274-2279; doi:10.1093/hmg/ddn128
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Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility
1 Arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK 2 School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield S10 2JF, UK 3 Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds LS7 4SA, UK 4 Clinical and Academic Rheumatology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK 5 Bone Research Group, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, UK 6 University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Oxford OX3 7LD, UK 7 WTCCC (Supplementary Note online) 8 YEAR Consortium (Supplementary Note online)
* To whom correspondence should be addressed. Tel: +44 1612751638; Fax: +44 1612755043; Email: anne.barton{at}manchester.ac.uk
Received February 15, 2008; Accepted April 15, 2008
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.
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