The human condition has many determinants. Although some of the most important are due to genetics, their fundamental contributions to various phenotypes are only apparent through gene expression. This is in large part determined by gene-environment interactions, some being ancestral and others occurring throughout the life-course. Such gene-environment interactions involve natural selection forces, resulting in inherited as well as epigenetic changes, which can also lead to intergenerational effects. Moreover, many human conditions, recognized as pathologic, chronic in nature, or evolving with age are polygenic in origin. They are determined not by a single gene (or a small number of genes), but by many genes collectively, imposing a biologic capacity (or incapacity) on an individual challenged with a particular environmental circumstance. Hallman and colleagues1 have provided a thoughtful overview of the current state of knowledge related to genomics and spontaneous preterm birth (SPTB) and have suggested that 25–40% may be hereditary. Moreover, they suggest that the maternal genome likely has more influence than the fetal genome on the risk of SPTB—but much remains unknown about how suspect genes identified by present genomic research might contribute to SPTB through various functional gene pathways. Nonetheless, they provide examples of candidate genes derived from recent findings,2,3 including selenocysteine-specific elongation factor (EEFSEC), WNT4, and HSPA1L, and suggest plausible gene pathways that may be relevant to defining the “clocks” that influence the risk of SPTB.

Hallman and colleagues1 also list factors associated with the onset of SPTB, including uterine distention, preterm prelabor (premature) rupture of membranes (PPROM), infection-activated inflammation, loss of immune tolerance, intrauterine bleeding, placental and fetal growth, fetal maturity, and the endocrine system. They suggest that current pharmacological approaches to prevent or delay SPTB using antibiotics, probiotics, tocolytic agents, or progesterone have had little impact on SPTB despite evidence supporting the contributions of each of these factors. This legacy of preventive failures sets the stage for the main focus of their review, which is on the genetic predisposition to SPTB as identified by genome-wide association studies (GWAS) or other genomic approaches. More importantly, they argue that molecular and translational studies are necessary to understand the functions of the identified genes that meet significance, as well as the gene pathways that might contribute. Ultimately, it is gene expression that is important. Thus, more information about the epigenome (the methylome) and processes involved with DNA replication and transcription or translation is needed. Other “omic” measures are also important for understanding such post-transcriptional and -translational events. Although many tools have been useful in identifying candidate genes (e.g., genome-wide linkage, whole exome sequencing), GWAS have been the predominant tool used. Nonetheless, the authors conclude that at least one GWAS3 was sufficiently large for its intended purpose. This is the study that identified EEFSEC, WNT4 and a few others as genes that might have relevance to SPTB. One concern with this approach is that the proximity of a single nucleotide polymorphism (SNP) to a particular gene does not necessarily mean that the mutation will affect a change in the transcription of that gene—the closest gene is not necessarily the one that is being regulated. This is especially true in the case of enhancers, which may be important for the regulation of genes at a distance from the identified SNP. Thus, the findings by Zhang and colleagues2 should not be considered definitive, but instead should be considered suggestive of genes that may or may not be involved in SPTB.

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