A genetic association study of the CLEC12A gene in rheumatoid arthritis

• Published in: Joint, bone, spine : revue du rhumatisme Vol. 79; no. 5; pp. 451 - 456
• Main Authors: Michou, Laëtitia, Cornélis, François, Levesque, Jean-Michel, Bombardieri, Stefano, Balsa, Alejandro, Westhovens, René, Barrera, Pilar, Alves, Helena, van de Putte, Leo, Migliorini, Paola, Bardin, Thomas, Petit-Teixeira, Elisabeth, Fernandes, Maria J.G
• Format: Journal Article
• Language: English
• Published: France Elsevier SAS 01.10.2012; Elsevier Masson
• Subjects: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid - epidemiology; Arthritis, Rheumatoid - ethnology; Arthritis, Rheumatoid - genetics; Candidate gene study; Case-Control Studies; CLEC12A gene; Cohort Studies; Europe - epidemiology; Female; Gene Frequency - genetics; Genetics; Genotype; Haplotype; Haplotypes - genetics; Human genetics; Humans; Internal Medicine; Lectins, C-Type - genetics; Life Sciences; Linkage Disequilibrium - genetics; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide - genetics; Receptors, Mitogen - genetics; Rheumatoid arthritis; Rheumatology; Single nucleotide polymorphism; Europe; Candidate gene study; CLEC12A gene; Single nucleotide polymorphism; Haplotype; Rheumatoid arthritis; Haplotypes; Rheumatoid; Gene Frequency; Humans; Middle Aged; Europe; Male; Genotype; Arthritis; Single Nucleotide; Case-Control Studies; Linkage Disequilibrium; 80 and over; Receptors; C-Type; Phenotype; Lectins; Adult; Female; Aged; Mitogen; Polymorphism; Cohort Studies
• ISSN: 1297-319X; 1778-7254
• DOI: 10.1016/j.jbspin.2011.12.012

Abstract Objective The CLEC12A gene codes for an immune inhibitory receptor that maps to 12p13.2 . Since an increase in CLEC12A mRNA correlates with rheumatoid factor values greater than 40 IU/ml in rheumatoid fibroblast-like synovial cells, this study assessed the potential of an association between CLEC12A and rheumatoid arthritis (RA) using a phenotype-based approach. Methods A discovery cohort of Western European ethnicity was genotyped for eight tag single nucleotide polymorphisms. Statistical analyses relied on the transmission disequilibrium test, relative risk and 95% confidence interval (CI) calculations. Observed haplotype frequencies were compared to expected frequencies using a family-based association test. Statistically significant associations were further tested in a second cohort of unrelated West-European RA patients. Results An overtransmission of the C allele of the rs1323461 tag single nucleotide polymorphism was observed (56.6% of allele C transmission, P = 0.046) in the discovery cohort. The relative risk of the AC and CC genotypes when compared to the AA genotype was high (relative risk = 4.08; 95% CI: 1.52–10.95, uncorrected P = 2.1 × 10−3 ), particularly in the subgroup of erosive RA (relative risk = 5.27; 95% CI: 1.53–18.19, uncorrected P = 2.1 × 10−3 ), both remaining statistically significant after conservative Bonferroni's correction. The CGAGCCGA haplotype was observed more frequently than expected ( P = 0.013). In the second cohort, the C allele had a tendency to be more frequent in RA patients (82.4%) than controls (79.2%) ( P = 0.069). Conclusion We report a potential genetic association of CLEC12A with RA. Since CLEC12A encodes for the myeloid inhibitory C-type lectin-like receptor that modulates cytokine synthesis, this receptor may contribute to the pathogenesis of RA.