An Integrated Omics Approach to Preterm Birth

Preterm birth (PTB; <37 weeks gestation) affects over 13 million births worldwide and over 350,000 in the U.S. annually. PTB cannot be fully explained by poor physical health or lack of prenatal care. Neighborhood characteristics have been related to psychological stress. Yet, the biological pathways by which neighborhood characteristics and psychological stress increase PTB risk remain unclear. Glucocorticoids (GCs) mediate the stress response, and the hypothalamic-pituitary-adrenal (HPA) axis controls GC secretion. Chronic stress exposures can dysregulate the HPA axis and alter GC levels. Pregnancy maintenance and parturition depend upon a delicate pro- and anti-inflammatory balance. GCs exert potent anti-inflammatory and immunosuppressive effects. In contrast, macrophage migration inhibitory factor (MIF), which is also released in response to stress, exhibits pro-inflammatory effects that override GC’s suppression of inflammation. Neighborhood characteristics are associated with greater inflammation and differential DNA methylation (DNAm) of inflammatory genes. Epigenome-wide and candidate gene studies reported relationships among maternal stressors, differential DNAm, and PTB. The combined effects of single nucleotide polymorphisms (SNPs) near DNAm sites may modify gene expression, potentially increasing PTB risk; but this possibility is unexplored. Integrated omic approaches may clarify mechanistic pathways to PTB by exploring integrated omic data sets. The goal of this study is to examine the relationships among types of neighborhood characteristics, psychological stress, integrated SNP and DNAm data, and PTB in pregnant women (90 PTB, 90 term births). We will leverage data from two related R01 studies (R01MD018293, MPI Giurgescu & Ohm; R01MD011575; PI Giurgescu). We will use demographic, neighborhood, psychological stress, and DNAm data, as well as DNA blood samples from the R01 studies. We will screen for SNP variants and combine SNP and DNAm data in an integrated analysis. We aim to: Aim 1. Identify PTB-associated SNPs in MIF-mediated GC regulation pathway genes between women with PTB and term births; Aim 2. (a) Identify differential DNAm of genes within the MIF-mediated GC regulation pathway in women with PTB compared to women with term births, and (b) Determine the extent to which differential DNAm of genes within the MIF-mediated GC regulation pathway associate with neighborhood characteristics, psychological stress, and gestational age at birth; and Aim 3. Explore the extent to which DNAm (Aim 2a) in the presence of SNPs (Aim 1) mediates the association of neighborhood characteristics and psychological stress with PTB. This study is the first step toward using integrated omics datasets to identify the biological phenotypes that increase risk for PTB. The award will provide the training required for an independent career focused on decreasing PTB.