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

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.

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).

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).

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