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


CONCLUSIONS
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.
Julià
Antonio
A
Institut de Recerca, Hospital Universitari Vall d'Hebrón, [corrected] Barcelona, Spain.
Ballina
Javier
J
Cañete
Juan D
JD
Balsa
Alejandro
A
Tornero-Molina
Jesus
J
Naranjo
Antonio
A
Alperi-López
Mercedes
M
Erra
Alba
A
Pascual-Salcedo
Dora
D
Barceló
Pere
P
Camps
Jordi
J
Marsal
Sara
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013030:Spain
C436492:KLF12 protein, human; D051741:Kruppel-Like Transcription Factors