Genetics and Genomics of Maternal Glycemia During Pregnancy

描述（由申请人提供）：发育中胎儿的宫内环境主要由母体代谢决定，不仅影响出生时的结局，还影响后期结局。患有糖尿病或妊娠期糖尿病（GDM）的母亲的后代在儿童期患代谢紊乱的风险增加，包括肥胖、糖耐量受损和血脂水平升高。母亲的血糖水平低于GDM的诊断可能会在儿童和成年后产生类似的风险。母体代谢由遗传和环境因素共同决定。作为确定影响母体代谢的因素的第一步，我们使用全基因组定位来确定与四个不同种族群体（北方欧洲血统、非洲-加勒比海、泰国和墨西哥-美国人）的母体代谢指标相关的遗传位点。这是使用作为高血糖和不良妊娠结局（HAPO）研究的一部分收集的DNA样本和表型数据完成的，该研究是一项观察性研究，旨在解决妊娠期高血糖症的严重程度低于显性糖尿病与不良母体和新生儿结局风险增加的独立相关性。跨四个种族组的荟萃分析鉴定了七个基因座，其证明了基因组范围内的显著性（即，p值< 5 × 10-8）与口服葡萄糖耐量试验期间母体空腹或2小时葡萄糖水平或空腹C肽相关。这些基因座中的两个以前没有被报道与全基因组关联研究中的代谢性状相关。我们现在建议建立在这些初步观察的基础上，通过解决常见的，低频率和罕见的遗传变异有助于定义的关联和许多因果变异的功能后果将改变基因表达的假设。为了解决这个假设，我们将执行以下具体目标。(1)使用靶向基因组捕获和下一代测序来识别四个相关基因座内的其他常见以及低频和罕见变异。这将使用来自北方欧洲血统、泰国人、墨西哥裔美国人和非洲裔加勒比海HAPO母亲的DNA进行，其中空腹或2小时葡萄糖或空腹C肽的值在特定性状的值的最低和最高十分位数中。(2)为进一步确定变体的优先级， 使用大量且全面的现有工具套件和实验上可用的功能基因组学数据集来推断每种变体的潜在功能。(3)使用高通量方法来定义目标2中优先考虑的变体的功能影响，重点关注那些预测会影响基因表达的变体。(4)为了证明具有功能影响的变体与不同的代谢性状相关，通过对鉴定的 来自四个种族群体的多达12，000名HAPO母亲的SNP。实现这些目标将为调节妊娠期间母体代谢的遗传因素提供基本的新见解，这对胎儿结局，更重要的是，对母亲及其后代的长期健康结局具有重要意义。

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.