Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

Abstract

BackgroundTwin studies have revealed a significant contribution of the fetal genome to risk of preterm birth. Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm delivery. Infection and inflammation of the fetal membranes is commonly found associated with PPROM.MethodsWe carried out whole exome sequencing (WES) of genomic DNA from neonates born of African‐American mothers whose pregnancies were complicated by PPROM (76) or were normal term pregnancies (N = 43) to identify mutations in 35 candidate genes involved in innate immunity and host defenses against microbes. Targeted genotyping of mutations in the candidates discovered by WES was conducted on an additional 188 PPROM cases and 175 controls.ResultsWe identified rare heterozygous nonsense and frameshift mutations in several of the candidate genes, including CARD6, CARD8, DEFB1, FUT2, MBL2, NLP10, NLRP12, and NOD2. We discovered that some mutations (CARD6, DEFB1, FUT2, MBL2, NLRP10, NOD2) were present only in PPROM cases.ConclusionsWe conclude that rare damaging mutations in innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by PPROM. These findings suggest that the risk of preterm birth in African‐Americans may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products.

Human β‐defensin‐1: A natural antimicrobial peptide present in amniotic fluid that is increased in spontaneous preterm labor with intra‐amniotic infection

“…The intra-amniotic inflammatory process associated with elevated amniotic fluid concentrations of HBD-1 may be mediated by toll-like receptors (TLRs) such as TLR-4 and TLR-2, which had been implicated in the mechanisms that lead to secretion of defensins by epithelial cells 169 . Our data, along with previous studies demonstrating that MIAC results in an increased amniotic fluid concentration of lactoferrin 81, 82 , lysozyme 19, 21 , and bacterial/permeability-increasing protein 20 among others 107, 170–172 , suggest that antimicrobial peptides participate in the soluble host defense mechanisms against intra-amniotic infection 173, 174 in women who underwent spontaneous preterm labor and delivered preterm.…”

Ascending Vaginal Infection Using Bioluminescent Bacteria Evokes Intrauterine Inflammation, Preterm Birth, and Neonatal Brain Injury in Pregnant Mice

“… 41 , 42 Furthermore, mutations in innate immunity and host defense genes in neonates are associated with an increased risk of preterm rupture of membranes. 43 …”

Inflammasome activation during spontaneous preterm labor with intra‐amniotic infection or sterile intra‐amniotic inflammation

“…[25][26][27][28][29][30][31][32] The mechanisms that lead to spontaneous preterm labor in the context of IAI or SIAI are thought to involve the inflammasome. [32][33][34][35][36][37][38][39] There are several types of inflammasomes that are named based on their sensor molecule. [40][41][42][43] Nucleotide-binding domain-like receptor (NLR) inflammasomes are cytoplasmic multiprotein complexes composed of (a) the sensor molecule (eg, NLR family pyrin domain-containing protein 3 or NLRP3), (b) the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) or PYD and CARD domain-containing protein (PYCARD), and (c) pro-caspase-1.…”