Impact of interaction between IL-21 gene variants and smoking status on susceptibility to rheumatoid arthritis.

Background: In recent years, interleukin-21 (IL-21) has been found to be a key player in RA pathogenesis and progression, despite accumulating evidence on rheumatoid arthritis (RA) etiology, the precise contribution of IL-21 gene variants interacting with environmental exposures remains unexplored in population-based studies. Therefore, we performed this study to evaluate the impact of gene single nucleotide polymorphisms (SNPs) and their interaction with environment on RA risk.

Methods: In this study, Genomic DNA was extracted from whole blood samples (Invitrogen PureLink™ Genomic DNA Mini Kit), and targeted genotyping of four SNPs (rs2055979, rs12508721, rs2221903 and rs907715) of IL-21 gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Genotypic relationship testing in this case-control study was performed by using SNPStats online software ( https://www.snpstats.net/ ), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The interaction combinations among four SNPs and environmental factors including smoking and alcohol drinking were screened using generalized multifactor dimensionality reduction (GMDR).

Results: Logistic regression analysis showed that the risks of RA were significantly higher in carriers with rs2055979- CA genotype (OR = 1.63, 95% CI = 1.28-1.97), rs2055979-AA genotype (OR = 2.02, 95% CI = 1.47-2.59), rs2055979-AA + CA genotype (OR = 1.78, 95% CI = 1.32-2.26), compared to carriers with rs2055979-CC genotype. In allele genetic model, rs2055979-A was also associated with increased RA risk (OR = 1.72, 95% CI = 1.39-2.06). However, we did not find any significant association of rs2221903, rs907715 and rs12508721 with RA risk. The GMDR model found a statistically significant two locus model (P = 0.018), including rs2055979 and smoking, indicating that the interaction between rs2055979 and smoking was significantly associated with the risk of RA. Smokers with rs2055979-AA or CA genotype had the highest risk of RA, compared with non-smokers with rs2055979-CC genotype, OR (95% CI) was 3.23 (1.86-4.64).

Conclusions: We found that rs2055979- A allele, gene- environment interaction between rs2055979 and smoking were all correlated with increased RA risk.