Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis

PLoS One. 2013 Aug 30;8(8):e72732. doi: 10.1371/journal.pone.0072732. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Cell Adhesion Molecules / genetics
  • Chemokine CCL2 / genetics
  • Demography
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Immunity, Cellular / genetics*
  • Lectins, C-Type / genetics
  • Male
  • Middle Aged
  • Multifactor Dimensionality Reduction
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, CCR2 / genetics
  • Receptors, Cell Surface / genetics
  • Risk Factors
  • Sex Characteristics*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*

Substances

  • CCL2 protein, human
  • CCR2 protein, human
  • CLEC7A protein, human
  • Cell Adhesion Molecules
  • Chemokine CCL2
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • Receptors, CCR2
  • Receptors, Cell Surface
  • dectin-2, mouse

Grant support

This study was partially supported by grants P08-CVI-4116 from Consejería de Salud de la Junta de Andalucia (Sevilla, Spain) and PI08/1051 and PI12/02688 from Fondo de Investigaciones Sanitarias (Madrid, Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.