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

Authors

Bhavi P. Modi, Virginia Commonwealth UniversityFollow
Maria E. Teves, Virginia Commonwealth University
Laurel N. Pearson, The Pennsylvania State University
Hardik I. Parikh, Virginia Commonwealth University
Piya Chaemsaithong, Eunice Kennedy Shriver National Institute for Child Health and Human Development
Nihar U. Sheth, Virginia Commonwealth University
Timothy P. York, Virginia Commonwealth University
Roberto Romero, Eunice Kennedy Shriver National Institute for Child Health and Human Development, University of Michigan, Michigan State University, Wayne State University
Jerome F. Strauss, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2017

Volume

12

Issue

3

DOI of Original Publication

10.1371/journal.pone.0174356

Comments

Originally published at https://doi.org/10.1371/journal.pone.0174356

Date of Submission

June 2017

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.

Rights

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Is Part Of

VCU Human and Molecular Genetics Publications