Prematurity is one of the most significant medical issues in the United States, costing the American health care system more than 26 billion dollars annually. Moreover, there are significant racial/ethnic disparities in the incidence of preterm birth, with African American women experiencing a disproportionately higher number preterm deliveries compared to European American women. Although the basis for this disparity is likely multi- factorial, there is increasing evidence that genetic variation and gene-environment interaction contribute to the increased risk of preterm birth in African Americans. One approach to elucidate risk factors for the disparity in prematurity, and also to identify targes for therapeutic intervention, is to search for genes that are associated or linked to this outcome. Genetic markers could be used to identify subjects prospectively who might benefit from early interventions. Markers predicting prematurity could also facilitate and reduce the cost of prevention clinical trials through identification of high-risk individuals and exclusion of low ris subjects. Finally, genetic markers could refine understanding of the normal as well as pathologic processes underlying parturition, and lead to innovative medical treatments based on contributing genes. The three Specific Aims proposed in this application represent an objective approach to identifying prematurity genes that contribute to ethnic/racial disparities. The focus will be on preterm premature rupture of membranes (PPROM), the leading identifiable cause of preterm birth and a pregnancy complication that is more frequent in African-Americans. We propose to: 1) Identify loci contributing to PPROM by admixture mapping (AM).
This Specific Aim i s grounded in the expectation that there are genes that make significant ancestry-specific contributions to risk of PPROM. The hypothesis to be tested is that African ancestry alleles as well as European ancestry alleles admixed into an African ancestry background contribute to risk of PPROM. Stated another way, ancestry and admixture can both make contributions to prematurity. 2) Identify candidate genetic variants lying under AM peaks by exome sequencing. To identify genetic variation in the AM peaks that potentially contribute to PPROM, as well as refine the AM, we will select 50 neonate cases and 50 neonate controls, whose African ancestry is similar (70- 80%), for exome sequencing of chromosomal regions underlying confirmed AM peaks. The hypotheses to be tested are: 1) Loci in the fetal genome on chromosomes 2,8,11,19 and 21 confer increased risk for PPROM~ 2) Loci on chromosome 21 confer risk and protection for PPROM in a population-specific manner~ 3) Risk genetic loci may act through epigenetic mechanisms (microRNAs) to promote PPROM. 3) Test candidate variants for linkage and association with PPROM using the transmission disequilibrium test (TDT). The goal of this Specific Aim is to test candidate genetic variants from regions identified in the feta (neonatal) AM and exome sequencing to determine if they are in association and linkage with PPROM, conferring risk or protection.
Prematurity is a major societal issue that costs the American health care system more than 26 billion dollars annually. There are significant disparities in the incidence of prematurity, with African American women experiencing a disproportionate number of preterm births. The proposed studies will utilize innovative genetic approaches to discover genes involved in disparities in preterm birth rates. This information will help identify women at risk of preterm birth and possibly lead to new prevention strategies.
|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|
|Modi, Bhavi P; Teves, Maria E; Pearson, Laurel N et al. (2017) Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM). Mol Genet Genomic Med 5:720-729|
|Lee, Eun D (2017) Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance? Placenta 56:40-43|
|Walsh, Scott W; Chumble, Anuja A; Washington, Sonya L et al. (2017) Increased expression of toll-like receptors 2 and 9 is associated with reduced DNA methylation in spontaneous preterm labor. J Reprod Immunol 121:35-41|
|Modi, Bhavi P; Washington, Sonya; Walsh, Scott W et al. (2017) Expression patterns of the chromosome 21 MicroRNA cluster (miR-99a, miR-125b and let-7c) in chorioamniotic membranes. Placenta 49:1-9|
|Frey, Heather A; Stout, Molly J; Pearson, Laurel N et al. (2016) Genetic variation associated with preterm birth in African-American women. Am J Obstet Gynecol 215:235.e1-8|
|Nunes, Vanessa; Cross, Jennifer; Speich, John E et al. (2016) Fetal membrane imaging and the prediction of preterm birth: a systematic review, current issues, and future directions. BMC Pregnancy Childbirth 16:387|
|Lee, Eun D; Brockett, Samone; Hilliard, DaShaunda et al. (2015) [172-POS]: Comparative expression profiling of endoplasmic reticulum aminopeptidase 2 and human leukocyte antigen-C expression in choriocarcinoma cell lines. Pregnancy Hypertens 5:88|
|York, Timothy P; Strauss 3rd, Jerome F; Eaves, Lindon J (2015) A narrow heritability evaluation of gestational age at birth. Hum Genet 134:809-11|
|York, Timothy P; Eaves, Lindon J; Neale, Michael C et al. (2014) The contribution of genetic and environmental factors to the duration of pregnancy. Am J Obstet Gynecol 210:398-405|
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