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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. 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.

Original publication

DOI

10.1038/ng.479

Type

Journal article

Journal

Nat Genet

Publication Date

12/2009

Volume

41

Pages

1313 - 1318

Keywords

Arthritis, Rheumatoid, CD2 Antigens, CD28 Antigens, CD58 Antigens, Case-Control Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Polymorphism, Single Nucleotide, Positive Regulatory Domain I-Binding Factor 1, Repressor Proteins, Risk Factors