GWA Mapping: Maternal Metabolism-Birth Weight Interactions

描述（由申请人提供）：低和高出生体重是新生儿发病率和死亡率的主要原因，流行病学数据已经建立了出生体重与成年后代谢疾病风险之间的关联。胎儿生长是由胎儿基因和母体子宫环境之间复杂的相互作用决定的。母体葡萄糖耐量的微妙或明显的变化，部分是由基因决定的，与出生时胎儿的大小有关。新出现的数据表明，胎儿的遗传变异可以影响母亲的新陈代谢。综上所述，我们假设在怀孕期间，母胎单位背景下的基因-环境相互作用会影响胎儿出生时的大小和母亲的新陈代谢。为了解决这一假设，我们建议对从母亲及其后代收集的约37,000个DNA样本进行基因组全关联（GWA）定位，这些样本是nih资助的高血糖和不良妊娠结局（HAPO）研究的一部分。HAPO是一项多中心的国际研究，在该研究中，使用统一的标准化方案，从25,000名不同种族和社会人口背景的孕妇中收集了与胎儿生长和母体葡萄糖代谢相关的高质量表型数据。我们建议对1500名婴儿及其欧洲血统的母亲进行基因分型，以实现以下具体目标：(1)应用分析方法对与出生时后代大小（出生体重、体重指数、头围和肥胖）相关的定量表型进行GWA定位研究，允许其他已知的影响，如胎龄、胎次和母亲体重增加。(2)应用上述方法确定影响妊娠~28周时母体葡萄糖耐量的遗传变异（空腹葡萄糖、口服葡萄糖耐量试验期间的葡萄糖和以数量性状表示的胰岛素敏感性），并考虑其他已知影响，如母体体重增加、胎次和年龄。(3)研究母体基因、宫内环境和胎儿基因之间的相互作用，以确定调节出生时大小的遗传调控和影响母体糖耐量的胎儿遗传变异的相互作用。将在更多的欧洲裔婴儿和母亲中进行一项重复研究，并计划在非洲-加勒比人、墨西哥裔西班牙人和泰国人中进行后续研究。

DESCRIPTION (provided by applicant): Low and high birth weights are a major cause of neonatal morbidity and mortality, and epidemiological data have established an association between birth weight and later risk of adult metabolic disease. Fetal growth is determined by complex interactions between fetal genes and the maternal uterine environment. Subtle or overt variation in maternal glucose tolerance which is, in part, genetically determined, is related to fetal size at birth. New emerging data suggest that genetic variation in the fetus can impact maternal metabolism. Given the above, we are hypothesizing that during pregnancy, gene-environment interactions in the context of the maternal-fetal unit impact fetal size at birth and maternal metabolism. To address this hypothesis, we are proposing to perform genome wide association (GWA) mapping on a subset of ~37,000 DNA samples that were collected from mothers and their offspring as part of the NIH-funded Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO is a multicenter, international study in which high quality phenotypic data related to fetal growth and maternal glucose metabolism has been collected from 25,000 pregnant women of varied racial and sociodemographic backgrounds using standardized protocols that were uniform across centers. We are proposing to genotype 1,500 infants and their mothers of European descent to accomplish the following specific aims: (1) To apply analytic approaches for conducting GWA mapping studies on quantitative phenotypes related to offspring size at birth (birth weight, ponderal index, head circumference and adiposity) allowing for other known influences such as gestational age, parity, and maternal weight gain. (2) To apply the above approaches to identify genetic variation that impacts maternal glucose tolerance at ~28 weeks of gestation (fasting glucose, glucose during an oral glucose tolerance test, and insulin sensitivity expressed as quantitative traits) allowing for other known influences such as maternal weight gain, parity and age. (3) To examine the interaction between maternal genes, the intrauterine environment, and fetal genes to identify interactions that modulate genetic regulation of size at birth and fetal genetic variation that impacts on maternal glucose tolerance. A replication study will be performed in additional infants and mothers of European descent with follow-up studies also planned in Afro-Caribbeans, Hispanics of Mexican descent and Thais.