Journal Article

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

Sheth, Nihar U., York, Timothy P., Strauss, Jerome F., Modi, Bhavi P., Parikh, Hardik I., Pearson, Laurel N., Chaemsaithong, Piya, Teves, Maria E., Romero, Roberto

2017

Overview

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225) of damaging/potentially damaging rare variants was identified in the genes of interest-fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / African Americans / Biology and Life Sciences / Birth / Birth rate / Childrens health / Collagen / Damage detection / Deoxyribonucleic acid / Disease / DNA / DNA sequencing / Epidemiology / Extracellular matrix / Female / Fetal Membranes, Premature Rupture - genetics / Fetuses / Fibrillar Collagens - genetics / Gene mutation / Gene sequencing / Genealogy / Genes / Genetic aspects / Genetic Predisposition to Disease / Genetics / Genomes / Genomics / Genotype / Genotyping / Gynecology / Humans / Hypotheses / Infant, Newborn / Infant, Premature / Medicine and Health Sciences / Membranes / Minority & ethnic groups / Mutation / Neonates / Obstetrics / People and places / Physiological aspects / Pregnancy / Pregnancy complications / Premature birth / Premature Birth - genetics / Premature rupture of the membrane / Proteins / Risk factors / Rupture / Rupturing / Statistical analysis / Statistical methods / Studies / Tensile strength / Twins / Young Adult