Identifying Regulatory Variants Associated with Maternal Hyperglycemia

识别与母亲高血糖相关的调节变异

基本信息

批准号：
8983217
负责人：
Cong Guo
金额：
$ 3.39万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-17 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8983217
关键词：
Adult Affect Alleles Binding Binomial Model Biological Assay Caribbean region Cell Line Cell model Child Childhood Chromosome Mapping Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Simulation DNA DNA-Protein Interaction Data Diabetes Mellitus Diagnostic Disease Electrophoretic Mobility Shift Assay Elements Environmental Risk Factor European Fetus Future Gene Expression Genes Genetic Genetic Variation Genetic study Genotype Gestational Diabetes Glucose Haplotypes Health HepG2 Hispanics Hour Human Hyperglycemia In Vitro Individual Introns Lead Libraries Life Lipids Measures Metabolic Metabolic Diseases Metabolism Methodology Methods Modeling Mothers Nucleic Acid Regulatory Sequences Obesity Outcome Pathway interactions Patients Phenotype Plasma Population Positioning Attribute Pregnancy Publishing Regulatory Element Reporter Research Risk Sampling Statistical Models System Testing Tissues Transcription factor genes Uncertainty Untranslated RNA Variant Woman Work Youth base cohort cost design genetic variant genome editing genome wide association study hexokinase impaired glucose tolerance in vivo novel novel diagnostics obesity risk offspring public health relevance trait transcription factor

项目摘要

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.

描述（由申请人提供）：妊娠期糖尿病 (GDM) 是在怀孕期间发生的糖尿病，影响约 3-10% 的母亲，患有糖尿病或 GDM 的母亲的后代有患肥胖症等代谢性疾病的风险。儿童期和以后的糖尿病对儿童的影响可能与诊断性 GDM 的风险相似。为了定义影响母亲代谢的遗传因素，我们使用了遗传因素。我们绘制了包含己糖激酶结构域 1 (HKDC1) 的基因座内的非编码遗传图谱，该基因座与妊娠期间 2 小时母体血糖水平相关。我们探索了这些非编码区域中的遗传变异通过基因表达发挥作用并预测母体。我们将在三个具体目标中测试这一假设，首先，我们的目标是使用高通量报告系统直接从供体 DNA 中识别功能性非编码遗传变异。确认不仅是常见的，而且是罕见的和个人的调节变异，并将它们与表型直接联系起来。其次，我们将利用我们的结果来生成一个模型，可以根据调节单倍型预测个体母亲的血糖水平。结果将是群体规模的关联。第三，我们将确定受调控变异影响的转录因子和基因，这可能会导致新的诊断标记和/或可药物靶点的发现，预期结果是我们将确定调控机制。调节母体血糖水平，并展示一种工作方法这样做将对识别有代谢疾病风险的母亲和下游研究的新途径产生直接的积极影响，同时，所开发的方法将可用于研究其他人类表型的调节机制，而无需原代组织。