Analysis of interleukin-18 promoter polymorphisms and changes in interleukin-18 serum levels underscores the involvement of interleukin-18 in recurrent spontaneous miscarriage

Objective: To evaluate the association of interleukin-18 (IL-18) promoter single-nucleotide polymorphisms rs1946519 (-656C/A), rs187238 (-137G/C), rs360718 (-119A/C), and rs360717 (-105G/A) and changes in IL-18 serum levels with recurrent spontaneous miscarriage (RSM). Design: Case-control study. Setting: Outpatient obstetrics and gynecology clinics. Patient(s): Women with confirmed RSM (n = 282), and 283 age-and ethnically matched controls. Intervention(s): None. Main Outcome Measure(s): IL-18 genotyping was accomplished by allelic discrimination assays; serum IL-18 levels were measured by ELISA. Result(s): The minor allele frequencies of rs360717 and rs1946519, but not rs360718 or rs187238, were higher in patients with RSM. Significant differences in the distribution of the rs360717 and rs1946519 genotypes were noted between patients and controls, and both rs360717 and rs1946519 IL-18 single-nucleotide polymorphisms showed significant association with RSM under additive, dominant, and recessive models. Lower serum IL-18 levels were seen between patients and controls and were more pronounced in rs360717 and rs1946519 heterozygous and homozygous genotypes. Four-locus (rs1946519/rs187238/rs360718/rs360717) IL-18 haplotype analysis identified that the AGAA (Pc<.001), CGAA (Pc<.001), and ACAG (Pc=.018) haplotypes were associated with a reduction in IL-18 secretion and with increased RSM risk, after adjustments for body mass index, menarche, and gravida. Conclusion(s): These results demonstrated that reduced IL-18 levels and rs360717 and rs1946519 IL-18 variants are significantly associated with RSM. (Fertil Steril (R) 2011; 96: 921-6. (C)2011 by American Society for Reproductive Medicine.)