Genetics and Genomics of Maternal Glycemia During Pregnancy

描述(申请人提供)：发育中的胎儿的宫内环境，主要由母亲的新陈代谢决定，不仅影响出生时的结果，而且也影响后来的结果。患有既往或妊娠期糖尿病(GDM)的母亲的后代在儿童时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较高。母亲的血糖水平低于诊断为妊娠期糖尿病的水平，可能会在儿童和成年后施加类似的风险。母体新陈代谢由遗传和环境因素共同决定。作为定义影响母体代谢的因素的第一步，我们使用全基因组图谱在四个不同的种族群体(北欧血统、非洲加勒比人、泰国人和墨西哥裔美国人)中确定了与母体新陈代谢测量相关的遗传位点。这项研究使用了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，该研究是一项观察性研究，旨在解决以下假设：妊娠期间的高血糖不像明显的糖尿病那么严重，与母亲和新生儿不良结局的风险增加独立相关。对四个种族群体进行的荟萃分析确定了七个基因座，它们在全基因组范围内与母亲的空腹或口服葡萄糖耐量试验中的2小时血糖水平或空腹C肽显著相关(即p值和lt；5x10-8)。在全基因组关联研究中，这些基因座中有两个尚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，解决这样的假设，即常见的、低频率的和罕见的遗传变异有助于确定的关联，并且许多因果变异的功能结果将是基因表达的改变。为了解决这一假设，我们将实现以下具体目标。(1)使用有针对性的基因组捕获和下一代测序来识别四个相关基因座中的其他常见以及低频和稀有变异。这将使用北欧血统、泰国、墨西哥裔美国人和非加勒比HAPO母亲的DNA来完成，这些母亲的空腹或2小时血糖或空腹C肽的值处于特定特征的最低和最高十进制。(2)确定变种的优先顺序，以便进一步 使用一套大型和全面的现有工具和公开可用的功能基因组数据集进行表征，以推断每个变体的潜在功能。(3)使用高通量方法来确定目标2中优先考虑的变体的功能影响，重点放在那些预测会影响基因表达的变体上。(4)通过对已识别的基因进行基因分型，证明具有功能影响的变异与不同的代谢性状有关 在来自四个种族群体的多达12000名额外的HAPO母亲中检测到SNPs。实现这些目标将提供对调节孕期母体新陈代谢的遗传因素的根本新见解，这对胎儿结局以及更重要的是对母亲及其后代的长期健康结果具有重要影响。

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.