Human Molecular Genetics Advance Access originally published online on July 31, 2009
Human Molecular Genetics 2009 18(21):4195-4203; doi:10.1093/hmg/ddp365
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Common and different genetic background for rheumatoid arthritis and coeliac disease
1 Department of Human Genetics, Institute for Genetic and Metabolic Diseases 2 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Genetics Department 4 Department of Rheumatology 5 Department of Epidemiology 6 Department of Pulmonology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 7 Department of Respiratory Diseases, Division of Heart and Lungs 8 Department of Radiology, Radiotherapy and Nuclear Medicine 9 Department of Paediatric Gastroenterology 10 Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands 11 Department of Gastroenterology, VU Medical Centre, Amsterdam, The Netherlands 12 Department of Paediatric Gastroenterology, Leiden University Medical Centre, Leiden, The Netherlands 13 Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK
* To whom correspondence should be addressed at: Department of Biomedical Genetics, University Medical Centre Utrecht, Stratenum 2.112, PO Box 85060, 3508 AB Utrecht, The Netherlands. Tel: +31 887568790; Fax: +31 887568479; Email: a.zhernakova{at}umcutrecht.nl
Received May 22, 2009; Accepted July 29, 2009
Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have commonalities in their pathogenesis. We aimed to replicate known RA loci in a Dutch RA population, and to investigate whether the effect of known RA and CD risk factors generalize across the two diseases. We selected all loci associated to either RA or CD in a GWAS and confirmed in an independent cohort, with a combined P-value cut-off P < 5 x 10–6. We genotyped 11 RA and 11 CD loci in 1368 RA patients, 795 CD patients and 1683 Dutch controls. We combined our results in a meta-analysis with UK GWAS on RA (1860 cases; 2938 controls) and CD (767 cases; 1422 controls). In the Dutch RA cohort, the PTPN22 and IL2/IL21 variants showed convincing association (P = 3.4 x 10–12 and P = 2.8 x 10–4, respectively). Association of RA with the known CD risk variant in the SH2B3 was also observed, predominantly in the subgroup of rheumatoid factor-positive RA patients (P = 0.0055). In a meta-analysis of Dutch and UK data sets, shared association with six loci (TNFAIP3, IL2/IL21, SH2B3, LPP, MMEL1/TNFRSF14 and PFKFB3/PRKCQ) was observed in both RA and CD cohorts. We confirmed two known loci and identified four novel ones for shared CD–RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.