GWA Mapping: Maternal Metabolism-Birth Weight Interactions

描述（由申请方提供）：出生体重偏低和偏高是新生儿发病率和死亡率的主要原因，流行病学数据已确定出生体重与成人代谢疾病后期风险之间存在关联。胎儿的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。母体葡萄糖耐量的细微或明显变化部分由遗传决定，与出生时胎儿的大小有关。新出现的数据表明，胎儿的遗传变异会影响母体的新陈代谢。鉴于上述情况，我们假设在妊娠期间，母胎单位背景下的基因-环境相互作用影响出生时的胎儿大小和母体代谢。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样本的子集进行全基因组关联（GWA）作图，作为NIH资助的Hyperlipidemia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，其中使用跨中心统一的标准化方案，从25，000名不同种族和社会人口学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1,500名欧洲血统的婴儿及其母亲进行基因分型，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作图研究，考虑其他已知的影响因素，如胎龄、产次和母亲体重增加。(2)应用上述方法鉴定影响妊娠约28周时母体葡萄糖耐量的遗传变异（空腹血糖、口服葡萄糖耐量试验期间的葡萄糖和胰岛素敏感性，以定量性状表示），考虑到其他已知影响，如母体体重增加、产次和年龄。(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节和影响母体葡萄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重复研究，还计划在非洲-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.