Polymorphism in intron 2 of the fetal interleukin-1 receptor antagonist genotype influences midtrimester amniotic fluid concentrations of interleukin-1β and interleukin-1 receptor antagonist and pregnancy outcome

Abstract

Objective Preterm labor in experimental models is initiated by intra-amniotic interleukin-1β (IL-1β) and inhibited by interleukin-1 receptor antagonist (IL-1ra). The IL-1ra gene is polymorphic and the different alleles are associated with variations in IL-1β and IL-1ra production. The relationship among the IL-1ra genotype of the fetus, concentrations of IL-1β and IL-1ra in second-trimester amniotic fluid, and pregnancy outcome was determined. Study design Amniotic fluids from 291 consecutive women with singleton pregnancies, obtained at 15 to 17 weeks' gestation, were tested for IL-1β and IL-1ra concentrations by enzyme-linked immunosorbent assay. DNA from fetal cells was analyzed for a length polymorphism in intron 2 of the IL-1ra gene by polymerase chain reaction. Pregnancy outcomes were obtained after completion of testing. Results The distribution of fetal IL-1ra genotypes was similar to that found in other populations: 50.9% (148) were homozygous for allele 1 (IL1RN ∗1), 39.5% (115) were IL1RN ∗1/allele 2 (IL1RN ∗2) heterozygotes, 6.9% (20) were IL1RN ∗2 homozygotes, whereas 2.7% (8) had combinations of other alleles. Fetal possession of IL1RN ∗2 was associated with a greater than 50% increase in midtrimester intra-amniotic IL-1β levels ( P = .006) and a smaller increase in IL-1ra levels ( P = .01) compared with fetuses who were IL1RN ∗1 homozygotes. Despite the low sample size, IL1RN ∗2 homozygosity, but not midtrimester intraamniotic levels of IL-1β and IL-1ra, was related to an increased rate of preterm birth ( P<.0001). In the 11 pregnancies that were subsequently terminated because of major malformations, there was a decreased frequency of IL1RN ∗1 homozygosity ( P = .04). Birth weight was unrelated to IL-1ra genotype. Conclusion Possession by the fetus of the IL1RN ∗2 allele is associated with enhanced intraamniotic IL-1β production. Induction of an intra-amniotic proinflammatory immune response might be more likely to lead to preterm labor in fetuses carrying the IL1RN ∗2 allele.