Inflammation-related gene polymorphisms and preterm delivery subtype in the Pregnancy Outcomes and Community Health Study

Genetic variability in pregnant women and/or their fetuses may influence the risk of preterm birth. The Pregnancy Outcomes and Community Health Study assessed eleven functional polymorphisms in nine genes involved in innate immune function. Within a subcohort, polymorphism results were tested for maternal and child interactions, gene environment interactions, and gene-gene interactions.;Maternal and Child Genotype Interactions (tested in ten polymorphisms). Among non-Hispanic white women, the risk of spontaneous preterm birth was highest in the group where both mother and child carried allele 2 of interleukin 1 receptor antagonist (IL-1RN) intron 2 repeat (odds ratio= 2.4; 95% confidence interval 1.3, 4.2). Among African American women, the risk of spontaneous preterm birth was highest when both mother and child carried the tumor necrosis factor receptor 2 198 G allele (odds ratio= 2.3; 95% confidence interval 1.0, 5.3). These finding suggest that carriage of a specific gene polymorphism by both mother and fetus may result in a synergy of susceptibility to preterm birth.;Vaginal Flora and Genotype Interactions (tested in three polymorphisms). Among non-Hispanic white and African-American women with both vaginal smear data and DNA, a Nugent Score ≥4 and tumor necrosis factor-alpha genotype -238 A/G or A/A was associated with an increased risk for preterm birth (race adjusted odds ratio= 2.6; 95% confidence interval 1.2, 5.8; p-value for genotype and vaginal flora interaction=0.02). There was no increased risk with just TNF-alpha genotype or Nugent Score. These findings suggest that the relationship between genotype and preterm birth may be strengthened in the presence of specific vaginal environments.;Gene-Gene Interactions (tested in eleven polymorphisms). The impact of gene-gene interactions on the risk of preterm birth was assessed with the use of multifactor dimensionality reduction. Two significant interactions were identified in non-Hispanic white women; a redundant interaction between IL-1 RN and interleukin-1 beta and a synergistic interaction between CD-14 and tumor necrosis factor receptor type II. These findings suggest that the clinical circumstances leading to preterm delivery may be indicative of biologically alternate pathways to preterm.;Future studies should continue to test the associations between inflammation-related gene and preterm birth diverse populations. As investigators develop models, careful consideration of phenotypic definition, interactions between genes and environment and interactions between maternal and fetal genotype along specific pathways to preterm birth will all be important in the search to understand causal mechanisms.