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 significant genetic variants responsible for spontaneous
preterm birth, at least in the context of pathologic
inflammation. The identification of genes that contribute to
preterm birth by whole exome sequencing, 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.