Letter abstract
Nature Genetics 40, 1216 - 1223 (2008)
Published online: 14 September 2008 | doi:10.1038/ng.233
Common variants at CD40 and other loci confer risk of rheumatoid arthritis
Soumya Raychaudhuri1,2,3, Elaine F Remmers4, Annette T Lee5, Rachel Hackett1, Candace Guiducci1, Noël P Burtt1, Lauren Gianniny1, Benjamin D Korman4, Leonid Padyukov6, Fina A S Kurreeman7, Monica Chang8, Joseph J Catanese8, Bo Ding9, Sandra Wong1, Annette H M van der Helm-van Mil7, Benjamin M Neale1,3,10, Jonathan Coblyn2, Jing Cui2, Paul P Tak11, Gert Jan Wolbink12,13, J Bart A Crusius14, Irene E van der Horst-Bruinsma15, Lindsey A Criswell16, Christopher I Amos17, Michael F Seldin18, Daniel L Kastner4, Kristin G Ardlie1,19, Lars Alfredsson9, Karen H Costenbader2, David Altshuler1,3, Tom W J Huizinga7, Nancy A Shadick2, Michael E Weinblatt2, Niek de Vries11, Jane Worthington20, Mark Seielstad21, Rene E M Toes7, Elizabeth W Karlson2, Ann B Begovich8, Lars Klareskog6, Peter K Gregersen5, Mark J Daly1,3 & Robert M Plenge1,2,3
To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls1, 2. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 
10-9 overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 10-7 overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 10-7 overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 10-6 overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 10-6 overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 10-8 overall).
- Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
- Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA.
- The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA.
- Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Solna, Stockholm 171 76, Sweden.
- Department of Rheumatology, Leiden University Medical Centre, Leiden 2333ZA, The Netherlands.
- Celera, Alameda, California 94502, USA.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK.
- Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam NL326, The Netherlands.
- Jan van Breemen Institute, Amsterdam 1056 AB, The Netherlands.
- Sanquin Research Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1006 AD, The Netherlands.
- Laboratory of Immunogenetics, Department of Pathology, Amsterdam 1007 MB, The Netherlands.
- Department of Rheumatology, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.
- Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, California 94143, USA.
- University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
- Rowe Program in Genetics, University of California at Davis, Davis, California 95616, USA.
- SeraCare Life Science, Cambridge, Massachusetts 02139, USA.
- Arthritis Research Campaign (arc)–Epidemiology Unit, Stopford Building, The University of Manchester, Manchester M13 9PT, UK.
- Genome Institute of Singapore, Singapore 138672.
Correspondence to: Robert M Plenge1,2,3 e-mail: rplenge@partners.org
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