FUNCTIONAL SIGNIFICANCE OF GENETIC VARIATION IN PREGNANCY

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ABSTRACT OF RESEARCH PLAN Premature birth represents a major problem in maternal and child health in the United States. Several converging lines of evidence suggest that premature birth is a complex syndrome involving the interplay of maternal as well as fetal genetic predispositions with environmental contexts, mediated by neuroendocrine, immune/inflammatory and vasculopathy-related pathways. The broad goal of our Program Project "Gene- Environment Interactions in Human Parfurif/on" is to identify the genetic and environmental determinants of the length of human gestation/timing of onset of spontaneous parturition, and to model the gene, environment and maternal-fetal interactions that may underlie the risk of premature birth among three racial/ethnic populations: African-Americans, Hispanics and nonHispanic Whites. Building, in part, on studies conducted in Project I to ascertain the extent and underlying population structure of maternal-fetal DNA sequence variation in key candidate genes that regulate the activity of the maternal-placental-fetal endocrine axis, and in Project II to model genotype-phenotype relationships to determine which combinations of maternal and fetal genotypes and environments are associated with measures of endocrine physiology and clinical outcome in each of the three racial/ethnic groups, the goal of Project III Is to determine the functional significance of specific maternal and fetal DNA sequence variations in three key candidate genes in human pregnancy with respect to the dynamics of stress- and parturition-related physiological processes. This project will characterize the in vivo functional significance of maternal and fetal genotypes in genes that are central to parturition as well as the stress response (corticotrophin-releasing hormone (CRH), glucocorticoid receptor (GR), CRH receptor-type 1 (CRHR,)) with respect to individual differences in pathophysiological responses to stress exposure in human pregnancy. The SPECIFIC AIMS are: 1) To determine the functional significance of maternal and fetal DNA sequence variations in the dynamics of biological stress responsivity in human pregnancy; and 2) To determine whether the functional effects of maternal and fetal DNA sequence variations on individual differences in biological stress responsivity in human pregnancy are moderated by context, with an emphasis on race/ethnicity. The project will be conducted at the University of California, Irvine, and will capitalize on the availability of a subject pool of 240 ethnically-diverse pregnant women and their fetuses/infants who are participants in an on-going, NIH-funded study of psychophysiological stress reactivity in pregnancy (HD-33506, P. Wadhwa, PI). The determination of the functional consequences of maternal and fetal genetic variation in key parturition- and stress-related genes will advance knowledge of these critical pathways leading to premature birth. The pattern of the multiple interacting genes and proteins in this physiological pathway will be elucidated. These studies may also identify potential therapeutic targets to reduce sensitivity to environmental and social stress in at-risk individuals, and specifically during pregnancy. This work will advance and have important implications for the growing awareness of the need to tailor individual treatment to individual patients based on individual DNA variations and contexts.