Maternal Obesity, Fetal Genomics, and Atherosclerotic Metabolic Risk
Principal Investigator: D Siscovick
Abstract: 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.
Funding Period: 2006-09-25 - 2010-08-31
more information: NIH RePORT
- Semiparametric maximum likelihood methods for analyzing genetic and environmental effects with case-control mother-child pair dataJinbo Chen
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Biometrics 68:869-77. 2012..We demonstrated the performance of our method through extensive simulation studies and the analysis of data from the Jerusalem Perinatal Study...
- Associations of maternal pre-pregnancy and gestational body size with offspring longitudinal change in BMIGabriella M Lawrence
Braun School of Public Health, The Hebrew University Hadassah Medical Center, Jerusalem, Israel
Obesity (Silver Spring) 22:1165-71. 2014..Associations of mppBMI and GWG with longitudinal change in offspring's BMI (ΔBMI) were examined, and whether associations are explained by offspring genetics was assessed...
- Maternal genetic variation accounts in part for the associations of maternal size during pregnancy with offspring cardiometabolic risk in adulthoodPandora L Wander
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America Department of Medicine, University of Washington, Seattle, Washington, United States of America
PLoS ONE 9:e91835. 2014..The extent to which maternal genetic variation accounts for these associations is unknown...
- Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral bloodGidon Toperoff
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel
Hum Mol Genet 21:371-83. 2012....
- Associations of maternal prepregnancy body mass index and gestational weight gain with adult offspring cardiometabolic risk factors: the Jerusalem Perinatal Family Follow-up StudyHagit Hochner
Hebrew University Hadassah, Braun School of Public Health, Jerusalem, Israel
Circulation 125:1381-9. 2012..However, whether these maternal attributes are related to other cardiometabolic risk factors in adulthood has not been comprehensively studied...