Identifying Regulatory Variants Associated with Maternal Hyperglycemia

Duke University, Durham NC

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Abstract

? DESCRIPTION (provided by applicant): Gestational diabetes mellitus (GDM), diabetes which occurs during pregnancy, affects about 3-10% of mothers. Offspring of mothers with pre-existing diabetes or GDM are at risk for developing metabolic disorders such as obesity and diabetes in childhood and later in life. Maternal glucose levels less than those of diagnostic GDM may impose similar risks to the child. Maternal metabolism is determined by both genetic and environmental factors. To define genetic factors that impact maternal metabolism, we used genetic mapping to identify non-coding genetic variants within a locus containing the gene hexokinase domain containing 1 (HKDC1) to be associated with 2 hour maternal glucose levels during pregnancy. We hypothesize that genetic variation in these non-coding regions act through altered gene expression and predict maternal glucose levels during pregnancy. We will test that hypothesis in three specific aims. First, we aim to identify functional non-coding geneti variants from directly from donor DNA using a high throughput reporter system. The advantage of assaying donor DNA directly is the ability to identify not only common, but also rare and personal regulatory variants and relate them directly with phenotype. Second, we will use our results to generate a model that can predict individual maternal glucose levels based on regulatory haplotypes. The outcome will be a population-scale association between allele-specific activity and phenotype. Third, we will identify transcription factors and genes that are affected by regulatory variation, which may lead to the discovery of new diagnostic markers and/or druggable targets. The expected outcomes are that we will identify regulatory mechanisms regulating maternal glucose levels, and demonstrate a working methodology in a patient cohort. Doing so will have immediate positive impacts on identifying mothers at risk for metabolic disease and new pathways for downstream studies. Meanwhile, the methods developed will be transferrable to study regulatory mechanisms of other human phenotypes without the need for primary tissues.