Genome-wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility

Arthritis Rheum. 2008 Aug;58(8):2275-86. doi: 10.1002/art.23623.


Objective: To identify new genes associated with susceptibility to rheumatoid arthritis (RA), using a 2-stage genome-wide association study.

Methods: Following a liability-based study design, we analyzed 317,503 single-nucleotide polymorphisms (SNPs) in 400 patients with RA and 400 control subjects. We selected a group of candidate SNPs for replication in an independent group of 410 patients with RA and 394 control subjects. Using data from the 3 previous genome-wide association studies in RA, we also looked for genomic regions showing evidence of common association signals. Finally, we analyzed the presence of genome-wide epistasis using the binary test implemented in the PLINK program.

Results: We identified several genomic regions showing evidence of genome-wide association (P < 1 x 10(-5)). In the replication analysis, we identified KLF12 SNP rs1324913 as the most strongly associated SNP (P = 0.01). In our study, we observed that this SNP showed higher significance than PTPN22 SNP rs2476601, in both the genome-wide association studies and the replication analyses. Furthermore, the integration of our data with those from previous genome-wide association studies showed that KLF12 and PTPRT are the unique loci that are commonly associated in 3 different studies (P = 0.004 and P = 0.002 for KLF12 in the Wellcome Trust Case Control Consortium study and the Brigham and Women's Rheumatoid Arthritis Sequential Study genome-wide association study, respectively). The genome-wide epistasis analysis identified several SNP pairs close to significance after multiple test correction.

Conclusion: The present genome-wide association study identified KLF12 as a new susceptibility gene for RA. The joint analysis of our results and those from previous genome-wide association studies showed genomic regions with a higher probability of being genuine susceptibility loci for RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / ethnology
  • Arthritis, Rheumatoid / genetics*
  • Case-Control Studies
  • Chromosome Mapping
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Spain


  • KLF12 protein, human
  • Kruppel-Like Transcription Factors