DESCRIPTION (provided by applicant): The intrauterine milieu of the developing fetus, as determined largely by maternal metabolism, impacts not only outcome at birth but later outcomes as well. Offspring of mothers with pre-existing or gestational diabetes mellitus (GDM) have an increased risk of metabolic disorders in childhood, including obesity, impaired glucose tolerance, and higher lipid levels. Maternal glucose levels less than those diagnostic of GDM may impose similar risks later in childhood and adulthood. Maternal metabolism is determined by both genetic and environmental factors. As a first step in defining factors that impact maternal metabolism, we used genome wide mapping to identify genetic loci associated with measures of maternal metabolism in four different race groups (Northern European ancestry, Afro-Caribbean, Thai, and Mexican-American). This was done using DNA samples and phenotype data collected as part of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, an observational study which addressed the hypothesis that hyperglycemia in pregnancy less severe than overt diabetes is independently associated with increased risk of adverse maternal and neonatal outcomes. Meta-analysis across the four race groups identified seven loci which demonstrated genome wide significant (i.e., p-value < 5 x 10-8) association with maternal fasting or 2 hr glucose levels or fasting C-peptide during an oral glucose tolerance test. Two of these loci have not previously been reported to be associated with metabolic traits in genome wide association studies. We now propose to build upon these initial observations by addressing the hypothesis that common, low frequency and rare genetic variants contribute to the defined associations and that the functional consequence of many of the causal variants will be altered gene expression. To address this hypothesis, we will perform the following specific aims. (1) To use targeted genomic capture and next generation sequencing to identify additional common as well as low frequency and rare variants within four of the associated loci. This will be done using DNA from Northern European ancestry, Thai, Mexican-American and Afro-Caribbean HAPO mothers with values of fasting or 2 hr glucose or fasting C- peptide in the lowest and highest deciles of values for the specific trait. (2) To prioritize variants for further characterization using a large and comprehensive suite of existing tools and publically available functional genomics datasets to infer potential function for each variant. (3) To use high throughput approaches to define the functional impact of variants prioritized in Aim 2, with a focus on those predicted to affect gene expression. (4) To demonstrate that variants which have a functional impact are associated with the different metabolic traits by genotyping the identified SNPs in up to 12,000 additional HAPO mothers from the four race groups. Accomplishing these aims will provide fundamental new insight into genetic factors regulating maternal metabolism during pregnancy which has important implications for fetal outcome and, more importantly, long- term health outcomes of both the mother and her offspring.

PUBLIC HEALTH RELEVANCE: Glucose levels in mothers during pregnancy have important implications for the offspring, as exposure of the developing fetus to high glucose levels is associated with adverse outcomes at birth as well as obesity and abnormal glucose metabolism later in childhood and adulthood. Factors regulating glucose levels during pregnancy are not well understood. The goal of this project is to define genetic factors that impact glucose levels and metabolism in mothers during pregnancy.