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Human Molecular Genetics Advance Access published online on April 22, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn128
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility

Anne Barton1,*, Wendy Thomson1, Xiayi Ke1, Steve Eyre1, Anne Hinks1, John Bowes1, Laura Gibbons1, Darren Plant1, Wellcome Trust Case Control Consortium7, Anthony G. Wilson2, Ioanna Marinou2, Ann Morgan3, Paul Emery3, YEAR consortium8, Sophia Steer4, Lynne Hocking5, David M. Reid5, Paul Wordsworth6, Pille Harrison6 and Jane Worthington1

1 arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK 2 School of Medicine & Biomedical Sciences, The University of Sheffield, Sheffield S10 2JF 3 Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, LS7 4SA 4 Clinical and Academic Rheumatology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS 5 Bone Research Group, Department of Medicine & Therapeutics, University of Aberdeen, UK, AB25 2ZD 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)

* Corresponding author Address: 1arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK Tel: 0044-161-275-1638 Fax: 0044-161-275-5043 e-mail: Anne.Barton{at}manchester.ac.uk

Received February 15, 2008; Revised April 14, 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 1,860 RA cases and 2,930 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, SNPs mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3,000 cases with disease and >3,000 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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