PADI4 polymorphism predisposes male smokers to rheumatoid arthritis

Objective To elucidate the differential role of peptidyl arginine deiminase 4 (PADI4) polymorphism in rheumatoid arthritis (RA) between Asian and European populations, possible gene-environmental interactions among the PADI4 polymorphism, sex and smoking status were analysed. Methods Three independent sets of case-control samples were genotyped for single-nucleotide polymorphisms in PADI4; Japanese samples (first set, 1019 RA patients, 907 controls; second set, 999 RA patients, 1128 controls) using TaqMan assays and Dutch samples (635 RA patients, 391 controls) using Sequenom MassARRAY platform. The association of PADI4 with RA susceptibility was evaluated by smoking status and sex in contingency tables and logistic regression models. Results In the first set of Japanese samples, PADI4 polymorphism (rs1748033) showed a greater risk in men (OR(allele) 1.39; 95% CI 1.10 to 1.76; p(trend) = 0.0054) than in women and in ever-smokers (OR(allele) 1.25; 95% CI 1.02 to 1.53; p(trend) = 0.032) than in never-smokers. Moreover, the highest risk was seen in male ever-smokers (OR(allele) 1.46; 95% CI 1.12 to 1.90; p(trend) = 0.0047). Similar trends were observed in the second set of Japanese samples as well as in Dutch samples. Conclusion PADI4 polymorphism highly predisposes male smokers to RA, and the genetic heterogeneity observed between Asian and European populations may be partly explained by differences in smoking prevalence among men.