Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk

Soumya Raychaudhuri, Brian P. Thomson, Elaine F. Remmers, Stephen Eyre, Anne Hinks, Candace Guiducci, Joseph J. Catanese, Gang Xie, Eli A. Stahl, Robert Chen, Lars Alfredsson, Christopher I. Amos, Kristin G. Ardlie, Anne Barton, John Bowes, Noel P. Burtt, Monica Chang, Jonathan Coblyn, Karen H. Costenbader, Lindsey A. CriswellJ. Bart A. Crusius, Jing Cui, Phillip L. de Jager, Bo Ding, Paul Emery, Edward Flynn, Pille Harrison, Lynne J. Hocking, Tom W. J. Huizinga, Daniel L. Kastner, Xiayi Ke, Fina A. S. Kurreeman, Annette T. Lee, Xiangdong Liu, Yonghong Li, Paul Martin, Ann W. Morgan, Leonid Padyukov, David M. Reid, Mark Seielstad, Michael F. Seldin, Nancy A. Shadick, Sophia Steer, Paul P. Tak, Wendy Thomson, Annette H. M. van der Helm-van Mil, Irene E. van der Horst-Bruinsma, Michael E. Weinblatt, Anthony G. Wilson, Gert Jan Wolbink, Paul Wordsworth, David Altshuler, Elizabeth W. Karlson, Rene E. M. Toes, Niek de Vries, Ann B. Begovich, Katherine A. Siminovitch, Jane Worthington, Lars Klareskog, Peter K. Gregersen, Mark J. Daly, Robert M. Plenge

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To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P <0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls(1). We used Gene Relationships Across Implicated Loci (GRAIL)(2), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci(1,3-11). We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall), CD28 (rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall) and PRDM1 (rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). An additional four were replicated (P <0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 x 10(-7) overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 x 10(-7) overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases
Original languageEnglish
Pages (from-to)1313-U76
JournalNature Genetics
Issue number12
Publication statusPublished - 2009

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