Preterm Premature rupture of the membranes (PPROM) is a major cause of preterm birth and perinatal morbidity/mortality. It has been hypothesized that pro-inflammatory cytokines are important mediators of PPROM. Cytokines induce expression of matrix metalloproteinases (MMPs) that degrade the extracellular matrix, which gives the membranes their tensile strength. We hypothesize that variation in pro-inflammatory cytokine and MMP genes contributes to the risk of PROM and that gene-environment interactions amplify the risk. The long-term goal of this research is to identify genes that make significant contributions to risk of preterm premature rupture of membranes (PPROM) and how infection interacts with these genes to increase the risk of the unfavorable obstetrical outcome.
Our specific aim are: 1) To determine if variation in the MMP-7 gene influences risk of PPROM. The hypothesis to be tested is that MMP-7 promoter alleles with stronger activity will be associated/linked with increased risk of PPROM. 2) To determine if variation in the IL-6 gene influences risk of PPROM. The hypothesis to be tested is that alleles that confer greater IL-6 expression will be associated/linked with increased risk of PPROM. 3) To determine if variation in the MMP-8 gene influences risk of PPROM. We will determine if there are polymorphisms in the MMP-8 promoter and if these variants affect MMP-8 promoter activity and influences risk of PPROM. 4) To determine if bacterial vaginosis and maternal or fetal genotype for the IL-6, MMP-7 or MMP-8 genes interact to affect the risk of PPROM. The hypothesis to be tested is that bacterial vaginosis will increase the risk of PPROM when the maternal or fetal genotypes include alleles with the strongest promoter activity. """"""""To address these aims we will conduct allelic association studies using a case-control design. The study population will be recruited from the obstetrical services of the Hospital San Borja Arriaran, Santiago, Chile (over 9,000 deliveries/year). The study will be restricted to Hispanic women, their partners and offspring. If positive results emerge from the association studies, we will examine linkage using the transmission disequilibrium test. Collectively, these studies could provide evidence for the contribution of genetic factors to the risk of preterm birth.
