Genetics and Genomics of Maternal Glycemia During Pregnancy

描述（由申请人提供）：胎儿发育的宫内环境主要由母体代谢决定，不仅影响出生时的结果，也影响后来的结果。患有糖尿病或妊娠期糖尿病（GDM）的母亲的后代在儿童期发生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的诊断水平，可能在儿童和成年后期造成类似的风险。母亲的新陈代谢是由遗传和环境因素共同决定的。作为确定影响母体代谢因素的第一步，我们使用全基因组图谱来确定与四个不同种族群体（北欧血统、加勒比黑人、泰国人和墨西哥裔美国人）的母体代谢测量相关的遗传位点。这项研究是利用DNA样本和表型数据进行的，这些数据是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，该研究提出了一个假设，即妊娠期低血糖比显性糖尿病更严重，与孕产妇和新生儿不良结局的风险增加独立相关。四个种族组的荟萃分析确定了7个位点，这些位点在全基因组范围内显示显著（即p值< 5 × 10-8）与口服葡萄糖耐量试验期间母体空腹或2小时血糖水平或空腹c肽相关。其中两个位点在全基因组关联研究中未被报道与代谢性状相关。我们现在建议在这些初步观察的基础上，通过解决常见、低频率和罕见的遗传变异有助于定义关联的假设，以及许多因果变异的功能后果将改变基因表达。为了解决这个假设，我们将实现以下具体目标。(1)使用靶向基因组捕获和下一代测序来识别四个相关位点内的其他常见、低频和罕见变异。这项研究将使用来自北欧血统、泰国、墨西哥裔美国人和加勒比黑人HAPO母亲的DNA，这些母亲的空腹或2小时葡萄糖或空腹C肽值处于特定性状值的最低和最高十分位数。(2)优先考虑进一步的变体

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.