Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk.
Raychaudhuri S., Thomson BP., Remmers EF., Eyre S., Hinks A., Guiducci C., Catanese JJ., Xie G., Stahl EA., Chen R., Alfredsson L., Amos CI., Ardlie KG., Barton A., Bowes J., Burtt NP., Chang M., Coblyn J., Costenbader KH., Criswell LA., Crusius JB., Cui J., De Jager PL., Ding B., Emery P., Flynn E., Harrison P., Hocking LJ., Huizinga TW., Kastner DL., Ke X., Kurreeman FA., Lee AT., Liu X., Li Y., Martin P., Morgan AW., Padyukov L., Reid DM., Seielstad M., Seldin MF., Shadick NA., Steer S., Tak PP., Thomson W., van der Helm-van Mil AH., van der Horst-Bruinsma IE., Weinblatt ME., Wilson AG., Wolbink GJ., Wordsworth P., Altshuler D., Karlson EW., Toes RE., de Vries N., Begovich AB., Siminovitch KA., Worthington J., Klareskog L., Gregersen PK., Daly MJ., Plenge RM.
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. We used Gene Relationships Across Implicated Loci (GRAIL), 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. 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.