Identifying Regulatory Variants Associated with Maternal Hyperglycemia

识别与母亲高血糖相关的调节变异

• 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
• 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

 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（由适用提供）：妊娠期发生在怀孕期间的糖尿病（GDM），影响约3-10％的母亲。患有糖尿病或GDM的母亲的后代有可能患上童年及以后生活的代谢疾病，例如肥胖和糖尿病。孕妇葡萄糖水平低于诊断GDM的葡萄糖水平可能对儿童施加类似的风险。孕产妇代谢取决于遗传和环境因素。为了定义影响遗传代谢的遗传因素，我们使用遗传学图来鉴定包含含1（HKDC1）基因己糖酶结构域（HKDC1）的基因座中的非编码遗传变异，与妊娠期间2小时有关。我们假设这些非编码区域中的遗传变异通过改变基因表达作用，并预测怀孕期间的遗产葡萄糖水平。我们将以三个特定目标来检验该假设。首先，我们旨在使用高通量报告基因系统直接从供体DNA中识别功能性非编码Geneti变体。直接组装供体DNA的优点不仅可以识别常见，而且可以识别稀有和个人调节变体，并将它们直接与表型联系起来。其次，我们将使用结果来生成一个模型，该模型可以根据调节单倍型来预测单个物物葡萄糖水平。结果将是等位基因特异性活性与表型之间的人群规模的关联。第三，我们将确定受调节差异影响的转录因子和基因，这可能导致发现新的诊断标记和/或可药物靶标。预期的结果是，我们将确定调节生物葡萄糖水平的调节机制，并在患者队列中证明一种工作方法。这样做将立即对确定有代谢疾病风险的母亲和下游研究的新途径产生积极影响。同时，开发的方法将被转移到研究其他人类表型的调节机制，而无需原代组织。