Spontaneous preterm birth: advances toward the discovery of genetic predisposition

Abstract

Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (eg, CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (eg, DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (ie, intraamniotic infection) or "danger signals" (alarmins) released during cellular stress or necrosis (ie, sterile intraamniotic inflammation). These findings support the notion that preterm birth has a polygenic basis that involves rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the whole exome sequencing-identified genes and other inflammatory conditions associated with preterm birth, such as periodontal disease and inflammatory bowel disease, was observed, which suggests a shared genetic substrate for these conditions. We propose that whole exome sequencing, as well as whole genome sequencing, is the most promising approach for the identification of functionally signi...

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.…”

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.…”

Replicated Umbilical Cord Blood DNA Methylation Loci Associated with Gestational Age at Birth

“…Investigators have observed a direct association of GA on newborn/umbilical cord DNAm 43,60,68,71,84 , including supervised algorithms designed to predict GA. 10,36,42 These studies are consistent with integrative approaches that have shown involvement of inflammatory and immune-related pathways 4,22,37 , and the larger picture of these pathways as being integral to the onset of labor. 65,66,73 Of the many potential antecedents, the literature defines a strong pathophysiological link for the causal role of inflammation on preterm birth. 64,66,80 While most histopathological cases of inflammation (e.g., chorioamnionitis) are sub-clinical, detection by molecular signatures responsible for the activation and enhancement of the innate immune response may provide an early warning sign.…”

“…While there has been some recent success in the identification of specific additive genetic loci that account for these estimates, the combined influence on risk to preterm birth from these studies has been small. 27,92,93 Emerging evidence for rare variants that influence risk promises larger effect sizes but for a small subset of births 53,73 and likely does not contribute directly to observed heritability estimates. 49 The impact of environmental sources on gestational age at birth is substantial 86 and varies dramatically across racial groups 12 that have markedly different preterm birth rates.…”

“…23,51,72 For the latter, investigators have recently suggested a provocative case for considering dysregulation in the genetic control of the inflammatory response and innate immune regulation due to pathogenic insults. 65,66,73 The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with GA. The validity of findings were assessed using two independent, racially mixed epidemiological cohorts.…”