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 only been 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 suggests that the nature and intensity of an inflammatory response in adults and children is under genetic control. Since 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 employed for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth.Candidate gene studies have sought genetic variants regulating inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome wide association studies (GWAS), an approach to identifying chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent GWAS including a large number of Caucasian 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 (WES), which examines the DNA sequence of protein coding regions of the genome. A recent WES study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (e.g., CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and anti-microbial peptide/proteins (e.g., DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (i.e. intra-amniotic infection) or “danger signals” (alarmins) released during cellular stress or necrosis (i.e. sterile intra-amniotic inflammation). These findings support the notion that preterm birth has a polygenic basis involving 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 WES-identified genes and other inflammatory conditions associated with preterm birth such as periodontal disease and inflammatory bowel disease was observed, suggesting a shared genetic substrate for these conditions.We propose that WES, as well as whole genome sequencing, is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous preterm birth, at least in the context of pathologic inflammation. The identification of genes contributing to preterm birth by WES, or whole genome sequencing, promises to yield valuable population specific biomarkers to identify the risk for spontaneous preterm birth and potential strategies to mitigate such a risk.
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