Human Molecular Genetics Advance Access originally published online on May 5, 2009
Human Molecular Genetics 2009 18(14):2693-2699; doi:10.1093/hmg/ddp193
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Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23
1 arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester M13 9PT, 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
* To whom correspondence should be addressed. Tel: +44 1612751674; Fax: +44 1612755043; Email: gisela.orozco{at}manchester.ac.uk
Received February 16, 2009; Revised April 1, 2009; Accepted April 27, 2009
The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 x 10–6, OR (95% CI) 1.22 (1.13–1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8–0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51–2.29)]. This equates to an effect size of 1.50 (95% CI 1.21–1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. 
Supplementary note online.