The genomics of preterm birth: from animal models to human studies

Abstract

Preterm birth (delivery at less than 37 weeks of gestation) is the leading cause of infant mortality worldwide. So far, the application of animal models to understand human birth timing has not substantially revealed mechanisms that could be used to prevent prematurity. However, with amassing data implicating an important role for genetics in the timing of the onset of human labor, the use of modern genomic approaches, such as genome-wide association studies, rare variant analyses using whole-exome or genome sequencing, and family-based designs, holds enormous potential. Although some progress has been made in the search for causative genes and variants associated with preterm birth, the major genetic determinants remain to be identified. Here, we review insights from and limitations of animal models for understanding the physiology of parturition, recent human genetic and genomic studies to identify genes involved in preterm birth, and emerging areas that are likely to be informative in future investigations. Further advances in understanding fundamental mechanisms, and the development of preventative measures, will depend upon the acquisition of greater numbers of carefully phenotyped pregnancies, large-scale informatics approaches combining genomic information with information on environmental exposures, and new conceptual models for studying the interaction between the maternal and fetal genomes to personalize therapies for mothers and infants. Information emerging from these advances will help us to identify new biomarkers for earlier detection of preterm labor, develop more effective therapeutic agents, and/or promote prophylactic measures even before conception.

Figure 1

Comparison of mouse and human parturition. (a) In mice, initial mechanisms for labor initiation include induction of uterine endometrial cyclooxygenase 1 (COX1) expression and reduction of uterine 15-hydroxyprostaglandin dehydrogenase (HPGD) expression. These changes in prostaglandin metabolism lead to elevated prostaglandin F_2α (PGF_2α), which acts on the ovarian corpus luteum to decrease circulating progesterone (P4). This systemic progesterone withdrawal results in induction of contraction-associated proteins (CAPs) and transition of the uterine myometrium from a quiescent to an actively contractile state. (b) In human pregnancy, labor initiation is associated with induction of amnion COX2 and placental corticotropin-releasing hormone (CRH) and a reduction in chorion HPGD. These changes in prostaglandin metabolism and peptide signaling are associated with increased amnion prostaglandin E₂ (PGE₂), pro-inflammatory cytokines and estradiol. This pro-inflammatory milieu is hypothesized to cause 'functional' progesterone withdrawal (circulating progesterone does not fall), or progesterone resistance, followed by induction of CAPs and labor. Note that several fundamental differences between human and mouse parturition exist beyond the differences in systemic progesterone regulation at term. Murine gestation is multi-fetal, whereas human gestation is predominantly single fetus. In mice, the sites of prostaglandin and progesterone synthesis are maternal, whereas in human pregnancy, the primary sites of prostaglandin and progesterone synthesis in late gestation are from fetal tissues. Adapted from [27], Ratajczak CK, Fay JC, Muglia LJ: Preventing preterm birth: the past limitations and new potential of animal models. Dis Model Mech 2010, 3:407-14 with permission from The Company of Biologists.

Figure 2

Two representations of affected status in the same pedigree with recurrent spontaneous preterm birth. Numbers indicate the gestational ages for each individual, in weeks. Circles indicate females and squares indicate males, diamonds indicate miscarriages. Preterm birth is indicated with closed (black) circles or squares, and question marks indicate unknown gestational ages. (a) Illustration of the pattern of affected status if the infant is proband for preterm birth. (b) Illustration of the pattern of affected status if the mother is proband for preterm birth. Modeling the incidence of maternal and infant phenotypes indicates that genetic influences on the timing of parturition are important and complex, and thus unlikely to be explained by a single gene model. Reproduced from [38] with permission from S Karger AG, Basel.