Mechanisms of Fetal Membrane Rupture

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Preterm premature rupture of the fetal membranes (PPROM) is a major cause of maternal morbidity and premature birth. Studies conducted during the current period of support revealed that polymorphisms in genes encoding matrix metalloproteinases (MMPs) contribute to risk of unscheduled membrane rupture. We now propose to 1) To determine whether variants in genes encoding proteins involved in collagen synthesis and posttranslational modification, including the SERPINH1 gene, which encodes a chaperone that regulates collagen synthesis, and the lysyl oxidase (LOX) gene family which catalyze collagen crosslinking, confer risk of PPROM. The hypotheses to be tested are that: 1) the ¿656 T allele of the SERPINH1 gene is an ethnic-selective factor contributing to preterm birth in African-Americans; 2) a 12 bp deletion adjacent to the ¿656 T SNP opposes the adverse effect of the ¿656 T allele on PPROM; 3) the 12 bp deletion increases SERPINH1 promoter activity mitigating the effect of the ¿656 T allele; 4) collagen synthesis is reduced in amnion fibroblasts carrying the ¿656 T allele, but not the ¿656 T allele in the presence of the 12 bp deletion; 5) the fibrillar collagen content of the amnion is reduced in carriers of the ¿656 T allele, but not when the 12 bp deletion is present; 6) the ¿656 T allele dose is correlated with amnion fibroblast collagen synthesis and amnion collagen content, as well as risk of PPROM; 7) that functional polymorphisms exist in the LOX gene family that result in altered gene expression or enzymatic activity and are associated with risk of PPROM; and 8) that these variants affect amnion collagen cross-linking. Based on preliminary data, attention will be focused on the LOXL1 gene. A twin-based study of the genetics of preterm birth will be incorporated as a new approach to establish heritability and gene finding. 2) To determine if epigenetic factors contribute to expression of PPROM candidate genes. The hypotheses to be tested are: 1) that variation in methylation of CpG islands in the promoters of MMP and collagen synthesis genes regulate gene expression; 2) that certain metyhylation marks result in allele-specific transcription; 3) that methylation status of amnion PPROM candidate genes varies among individuals; 4) that methylation patterns of these genes that influence transcription are associated with risk of PPROM; 5) that epigenetic marks modify the impact of genetic variation. This hypothesis will be tested using the MMP1 promoter ¿930 T/C SNP as an exemplar. The proposed studies represent a synthesis of clinical and laboratory research that will encompass molecular and biochemical analyses that relate to the genetic variants under investigation. These studies will disclose genetic and epigenetic factors that contribute to PPROM including racial/ethnic disparity in preterm birth, allow the identification of women at risk of PPROM, and identify genetic markers predicting PPROM.