Maternal and Fetal Genetic Contributions to Preterm Birth

Abstract

Preterm birth is a major public health issue, affecting approximately 10% of pregnancies in the United States. The causes of preterm birth include the genetics of the mother, the genetics of the fetus, the environment, and the interplay of any combination of these factors. Maternal genetics is a significant contributor to preterm birth but few genome wide association studies (GWAS) have identified associated genetic variants. Recently, the largest GWAS on preterm birth to date found several loci associated with preterm birth that suggest impaired decidualization of the endometrium may play a role. To investigate regulatory activity in genomic regions identified via GWAS, we used the massively parallel reporter assay STARR-seq. Motifs enriched in peaks of significant activity include many transcription factors known to have critical roles in decidualization of the endometrium. An additional factor leading to preterm birth is maternal psychological stress. Maternal psychological stress is particularly linked to PPROM, the leading identifiable cause of preterm birth. PPROM is a pregnancy complication in which the chorion and amnion weaken and rupture prior to 37 weeks of pregnancy and before contractions have begun. PPROM is responsible for 30-40% of preterm birth cases. PPROM is closely linked to maternal psychological stress, leading us to hypothesize that glucocorticoid signaling may contribute to PPROM. As a step towards testing that hypothesis, we investigated the gene expression effects of glucocorticoids in primary amnion cells using RNA-seq. KCNA5 emerged as a potential GR regulated gene. KCNA5 has previously been reported to be a cell stress sensor that regulates proliferation and apoptosis. KCNA5 knockdown significantly increased cell proliferation without appearing to impact apoptosis and CRISPR-mediated over expression of endogenous KCNA5 decreased in cell proliferation. Taken together, these results suggest that glucocorticoid-mediated activation of KCNA5 contributes to decreased cell proliferation in the amnion epithelium. Decreases in amnion epithelial proliferation could impair the ability of these cells to repair microfractures in the membrane and lead to overall membrane weakening. We were able to study endocrine responses in pregnancy relevant cells to understand more broadly how these interactions affect preterm birth. Greater understanding of the interaction between preterm birth risk factors will move our understanding of the field forward.