title: 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.
abstract: 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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Bhavi P
authors.identifier: http://orcid.org/0000-0003-1758-2847
authors.initials: BP
authors.lastname: Modi
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Teves
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, PA, United States of America.
authors.forename: Laurel N
authors.initials: LN
authors.lastname: Pearson
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Hardik I
authors.initials: HI
authors.lastname: Parikh
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH, Bethesda, MD and Detroit, MI, United States of America.
authors.forename: Piya
authors.initials: P
authors.lastname: Chaemsaithong
authors.affiliation: Center for Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Nihar U
authors.initials: NU
authors.lastname: Sheth
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.|Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: York
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH, Bethesda, MD and Detroit, MI, United States of America.|Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States of America.|Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States of America.|Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.|Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D000328:Adult; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics*; D024022:Fibrillar Collagens / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D009154:Mutation; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D055815:Young Adult
chemical_list: D024022:Fibrillar Collagens