There is mounting evidence that maternal obesity (MO) influences both fetal development and adult atherosclerotic metabolic risk (AMR), due to obesity-related metabolic diseases, such as diabetes, hypercholesterolemia, and high blood pressure. However, the mechanisms that account for the associations of MO with AMR remain unknown. Using data from a unique, population-based, birth cohort and a 30-year follow-up examination, we propose to examine (1) whether the association of MO and AMR is due, at least in part, to common maternal and/or fetal genetic variation in a set of candidate genes from distinct molecular pathways, and (2) whether maternal and/or fetal genetic variation influences the MO- AMR relation through an effect on the intra-uterine environment and fetal growth. The Jerusalem Perinatal Study (JPS) collected extensive prenatal, perinatal, and postnatal data from births from 1974-76. We now propose to add new phenotypic and genotypic data from mothers and offspring to the existing archival data. We will recruit a sub-cohort of mothers (n =1500) and their offspring born from 1974-76 (n = 1500), reflecting the full range of MO and BW. We will determine whether maternal and fetal genetic variation in sets of candidate genes in molecular pathways, such as insulin sensitivity and insulin signaling, adipocyte homeostasis and hypothalamic-pituitary-adrenal (HPA) axis, and the appetite regulatory neural network, account for the associations of MO with AMR in young adults, ages 30-32, through an effect on intra- uterine growth. In a series of nested models, we will distinguish the effects of common maternal and fetal genetic variation that has the potential to alter the intra-uterine environment, from post-natal effects of offspring genetic variation and non-genetic effects of MO on adult AMR, after taking into account the effects of other factors, such as maternal smoking and breast feeding. We also will examine potential interactions of MO with maternal and fetal genetic variation on the development of AMR. The research is designed to explore several promising mechanistic pathways, using measures of human maternal and fetal genomic variation, in the context of MO, intra-uterine growth, and other pre- and post-natal clinical characteristics. The long-term goals of the proposed study are to identify potential mechanistic targets for interventions to prevent the consequences of MO on the intra-uterine environment and adult AMR.
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