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

Nat Genet. 2009 Dec;41(12):1313-8. doi: 10.1038/ng.479. Epub 2009 Nov 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • CD2 Antigens
  • CD28 Antigens
  • CD58 Antigens
  • Repressor Proteins
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1