Preterm premature rupture of the fetal membranes (PPROM) is a major cause of premature birth and neonatal morbidity and mortality. This obstetrical complication is more prevalent in African-Americans, although the underlying causes for this disparity are currently unknown. We 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 which catalyzes collagen cross-linking, 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) the -656 T allele has diminished promoter activity in fetal amnion fibroblasts;3) a 12 bp deletion adjacent to the -656 T SNP opposes the adverse effect of the -656 T allele on PPROM;4) the 12 bp deletion increases SERPINH1 promoter activity mitigating the effect of the -656 T allele;5) 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;6) 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;7) the -656 T allele dose is correlated with amnion fibroblast collagen synthesis and amnion collagen content, as well as risk of PPROM;8) that functional polymorphisms exist in the LOX gene that result in altered gene expression or enzymatic activity and are associated with risk of PPROM;and 9) that these variants affect amnion collagen cross-linking. 2) Determine whether epigenetic factors alter MMP expression leading to PPROM. 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 methylation 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 racial/ethnic disparity in preterm birth, allow the identification of women at risk of PPROM, and identify genetic markers predicting PPROM.

National Institute of Health (NIH)
National Institute on Minority Health and Health Disparities (NIMHD)
Comprehensive Center (P60)
Project #
Application #
Study Section
Special Emphasis Panel (ZMD1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
United States
Zip Code
Saluja, Saurabh; Nwomeh, Benedict; Finlayson, Samuel R G et al. (2018) Guide to research in academic global surgery: A statement of the Society of University Surgeons Global Academic Surgery Committee. Surgery 163:463-466
Hawn, Sage E; Sheerin, Christina M; Webb, Bradley T et al. (2018) Replication of the Interaction of PRKG1 and Trauma Exposure on Alcohol Misuse in an Independent African American Sample. J Trauma Stress 31:927-932
Sosnowski, David W; Booth, Carolyn; York, Timothy P et al. (2018) Maternal prenatal stress and infant DNA methylation: A systematic review. Dev Psychobiol 60:127-139
Jayaraman, Sudha P; Anand, Rahul J; DeAntonio, Jonathan H et al. (2018) Metabolomics and Precision Medicine in Trauma: The State of the Field. Shock 50:5-13
Strauss 3rd, Jerome F; Romero, Roberto; Gomez-Lopez, Nardhy et al. (2018) Spontaneous preterm birth: advances toward the discovery of genetic predisposition. Am J Obstet Gynecol 218:294-314.e2
Kinser, Patricia Anne; Thacker, Leroy R; Lapato, Dana et al. (2018) Depressive Symptom Prevalence and Predictors in the First Half of Pregnancy. J Womens Health (Larchmt) 27:369-376
Walsh, Scott W; Nugent, William H; Solotskaya, Anna V et al. (2018) Matrix Metalloprotease-1 and Elastase Are Novel Uterotonic Agents Acting Through Protease-Activated Receptor 1. Reprod Sci 25:1058-1066
Sheerin, Christina M; Lind, Mackenzie J; Brown, Emily A et al. (2018) The impact of resilience and subsequent stressful life events on MDD and GAD. Depress Anxiety 35:140-147
Modi, Bhavi P; Parikh, Hardik I; Teves, Maria E et al. (2018) Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth. BMC Med Genet 19:181
Modi, Bhavi P; Teves, Maria E; Pearson, Laurel N et al. (2017) Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes. PLoS One 12:e0174356

Showing the most recent 10 out of 91 publications