Genetics and Genomics of Maternal Glycemia During Pregnancy

孕期母亲血糖的遗传学和基因组学

• 批准号: 8726979
• 负责人: William L Lowe
• 金额: $ 15.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726979
• 关键词: Accounting; Address; Adult; Affect; American; Birth; Birth Weight; C-Peptide; Caribbean region; Childhood; Complex; Consensus; DNA; Data; Data Collection; Data Set; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Enrollment; Environmental Risk Factor; European; Fasting; Fetus; Frequencies; Funding; Gene Expression; Genetic; Genetic Research; Genomics; Genotype; Gestational Diabetes; Glucose; Goals; Health; Human Genetics; Human Resources; Hyperglycemia; Laboratories; Lipids; Maps; Measures; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolism; Mexican Americans; Mothers; Neonatal; Newborn Infant; OGTT; Obesity; Observational Study; Outcome; Outcome Study; Phenotype; Pregnancy; Pregnancy Outcome; Protocols documentation; Race; Reporting; Risk; Sampling; Serum; Third Pregnancy Trimester; Training; United States National Institutes of Health; Variant; Woman; adverse outcome; base; cohort; comparative genomics; disease phenotype; disorder risk; fetal; functional genomics; genetic variant; genome wide association study; genome-wide; glucose metabolism; glucose tolerance; impaired glucose tolerance; insight; instrument; next generation sequencing; obesity risk; offspring; public health relevance; rare variant; tool; trait

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.

描述（由申请人提供）：在很大程度上由孕产妇的代谢确定，发育中的胎儿的宫内环境不仅会影响出生时的结果，还影响后来的结果。患有先前存在或妊娠糖尿病（GDM）的母亲的后代具有童年代谢疾病的风险增加，包括肥胖症，葡萄糖耐受性受损和脂质水平较高。孕妇葡萄糖水平低于GDM诊断的母体葡萄糖水平可能会在儿童期和成年期间施加类似的风险。孕产妇代谢取决于遗传和环境因素。作为定义影响母体代谢的因素的第一步，我们使用了基因组广泛的映射来识别与四个不同种族群体（北欧血统，非洲裔加勒比海，泰国，泰国和墨西哥裔美国人）相关的遗传基因座。这是使用DNA样品和表型数据作为高血糖和不良妊娠结局（HAPO）研究的一部分收集的，这是一项观察性研究，该研究解决了以下假设：妊娠高血糖症的严重程度低于明显的糖尿病与不良母亲和新生儿的不良风险独立相关。四个种族组的荟萃分析确定了七个基因座，在口服葡萄糖耐受性测试期间，与母体禁食或2小时的葡萄糖水平或2小时的葡萄糖水平或禁食C肽相结合，证明了七个基因群（即P值<5 x 10-8）。这些基因座中的两个以前没有据报道与基因组广泛关联研究中的代谢特征有关。现在，我们建议通过解决以下假设，即常见，低频和罕见的遗传变异有助于定义的关联，并且许多因果变体的功能后果将改变基因表达。为了解决这一假设，我们将执行以下特定目标。 （1）使用靶向基因组捕获和下一代测序来识别相关基因座的四个基因座中的其他常见和低频和稀有变体。这将使用来自北欧血统，泰国，墨西哥裔美国人和非洲 - 加勒比海hapo母亲的DNA，其含量为禁食或2小时葡萄糖或禁食的C-肽，在特定特征的最低和最高分数中。 （2）优先考虑变体以进一步 使用大量而全面的现有工具和公开可用功能基因组学数据集的表征来推断每个变体的潜在功能。 （3）使用高吞吐量方法来定义AIM 2中优先级的变体的功能影响，重点是预测会影响基因表达的功能。 （4）证明具有功能影响的变体通过基因分型来与不同的代谢性状有关 来自四个竞赛组的Hapo母亲多达12,000名。实现这些目标将为调节孕妇新陈代谢的遗传因素提供基本的新见解，这对胎儿结局具有重要意义，更重要的是，母亲和她的后代的长期健康结果。