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The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of  Dectin-2   rs4264222T  allele had an increased risk of RA (OR = 1.47, 95%CI 1.10–1.96) whereas patients harboring the  DC-SIGN   rs4804803G ,  MCP-1   rs1024611G ,  MCP-1   rs13900T  and  MCP-1   rs4586C  alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49–0.88; OR = 0.66, 95%CI 0.50–0.89; OR = 0.73, 95%CI 0.55–0.97 and OR = 0.68, 95%CI 0.51–0.91). Interestingly, significant gender-specific differences were observed for  Dectin-2   rs4264222  and  Dectin-2   rs7134303 : women carrying the  Dectin-2   rs4264222T  and  Dectin-2   rs7134303G  alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34–2.79 and OR = 1.90, 95%CI 1.29–2.80). Also five other SNPs showed significant associations only with one gender: women carrying the  MCP-1   rs1024611G ,  MCP-1   rs13900T  and  MCP-1   rs4586C  alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43–0.87; OR = 0.67, 95%CI 0.47–0.95 and OR = 0.60, 95%CI 0.42–0.86). In men, carriers of the  DC-SIGN   rs2287886A  allele had an increased risk of RA (OR = 1.70, 95%CI 1.03–2.78), whereas carriers of the  DC-SIGN   rs4804803G  had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32–0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for  Dectin-2   rs4264222 ,  MCP-1   rs1024611 ,  MCP-1   rs13900  and  DC-SIGN   rs4804803  polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08–1.77; OR = 0.74, 95%CI 0.58–0.94; OR = 0.76, 95%CI 0.59–0.97 and OR = 0.56, 95%CI 0.34–0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant two-locus interaction model in women that was not seen in men. This model consisted of  Dectin-2   rs4264222  and  Dectin-2   rs7134303  SNPs and suggested a synergistic effect between the variants. These findings suggest that  Dectin-2 ,  MCP-1  and  DC-SIGN  polymorphisms may, at least in part, account for gender-associated differences in susceptibility to RA.

Gender-Specific Effects of Genetic Variants within Th1 and Th17 Cell-Mediated Immune Response Genes on the Risk of Developing Rheumatoid Arthritis