Genetic association between the PRKCH gene encoding protein kinase Cη isozyme and rheumatoid arthritis in the Japanese population

Objective. Analyses of families with rheumatoid arthritis (RA) have suggested the presence of a putative susceptibility locus on chromosome 14q2l-23. This large population-based genetic association study was undertaken to examine this region. Methods. A 2-stage case-control association study of 950 unrelated Japanese patients with RA and 950 healthy controls was performed using > 400 gene-based common single-nucleotide polymorphisms (SNPs). Results. Multiple SNPs in the PRKCH gene encoding. the eta isozyme of protein kinase C (PKC eta) showed significant single-locus disease associations, the most significant being SNP c.427 + 8134C > T (odds ratio 0.72, 95% confidence interval 0.62-0.83, P = 5.9 x 10(-5)). Each RA-associated SNP was consistently mapped to 3 distinct regions of strong linkage disequilibrium (i.e., linkage disequilibrium or haplotype blocks) in the PRKCH gene locus, suggesting that multiple causal variants influence disease susceptibility. Significant SNPs included a novel common missense polymorphism of the PRKCH gene, V374I (rs2230500), which lies within the ATP-binding site that is highly conserved among PKC superfamily members. In circulating lymphocytes, PRKCH messenger RNA was expressed at higher levels in resting T cells (CD4+ or CD8+) than in B cells (CD19+) or monocytes (CD14+) and was significantly down-regulated through immune responses. Conclusion. Our results provide evidence of the involvement of PRKCH as a susceptibility gene for RA in the Japanese population. Dysregulation of PKC eta signal transduction pathway(s) may confer increased risk of RA through aberrant T cell-mediated autoimmune responses.