Interleukin-18 promoter polymorphisms and risk of idiopathic recurrent pregnancy loss in a Tunisian population

IL-18 is a pro-inflammatory cytokine that regulates the differentiation and effector functions of CD4+ (Th1) and CD8+ (CTL) T cells, which are implicated in the pathogenesis of recurrent pregnancy loss (RPL). We investigated the association of the IL-18 gene promoter single nucleotide polymorphisms (SNPs) −656C/A (rs1946519), −137G/C (rs187238), −119A/C (rs360718), and −105G/A (rs360717), by TaqMan assays in analysis in 470 Tunisian women comprising 235 RPL cases and 235 multi-parous controls. The association of IL-18 alleles, genotypes, and haplotypes with RPL was evaluated by Fisher's exact test and regression analysis. The frequency of minor alleles −105G/A (P < 0.001) and −656C/A (P < 0.001), but not −119A/C (P = 0.93) or −137G/C (P = 0.32), were higher in RPL cases. Significant differences were also noted in the genotype distribution of −105G/A (P < 0.001) and −656C/A (P < 0.001) between cases and controls. Four-locus (−656C/A, −137G/C, −119A/C, −105G/A) IL-18 haplotype analysis identified AGAA (corrected P < 0.001), and CGAA (corrected P < 0.001) haplotypes to be associated with increased RPL risk, after adjusting for age and BMI. These results demonstrate that −105G/A and −656C/A IL-18 variants are significantly associated with RPL.