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

• Published in: Arthritis and rheumatism 2008-08, Vol.58 (8), p.2275-2286
• Main Authors: Julià, Antonio, Ballina, Javier, Cañete, Juan D., Balsa, Alejandro, Tornero‐Molina, Jesus, Naranjo, Antonio, Alperi‐López, Mercedes, Erra, Alba, Pascual‐Salcedo, Dora, Barceló, Pere, Camps, Jordi, Marsal, Sara
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid - ethnology; Arthritis, Rheumatoid - genetics; Biological and medical sciences; Case-Control Studies; Chromosome Mapping; Diseases of the osteoarticular system; Female; Genetic Predisposition to Disease; Humans; Inflammatory joint diseases; Kruppel-Like Transcription Factors - genetics; Male; Medical sciences; Middle Aged; Polymorphism, Single Nucleotide - genetics; Spain
• ISSN: 0004-3591; 1529-0131
• 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 × 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.