Predicting Newborn and Childhood Adiposity: An Integrated Omics Approach

儿童肥胖症和相关代谢紊乱的患病率正在增加。及早识别 面临儿童肥胖风险的子女对于启动早期预防干预至关重要。儿童肥胖症 由遗传和环境因素的复杂组合决定。其中重要的是宫腔内。 环境，因为它影响胎儿肥胖症，我们的初步数据显示，这与童年高度相关 肥胖症。因此，确定胎儿脂肪增加的重要因素是一个关键的挑战。我们建议解决以下问题 孕期母体代谢物和代谢网络影响新生儿肥胖的假说 不同程度取决于胎儿的遗传易感性，并最终影响儿童 肥胖与新陈代谢健康。我们的目标是确定与以下物质相关的代谢物和代谢途径 并确定这些关联是否受胎儿基因变异的影响。 然后，这些数据将被用来开发一个早期预测胎儿和儿童肥胖的模型。我们会 使用表型数据、血清样本和来自登记的母亲及其子女的DNA来完成这一点 高血糖与不良妊娠结局(HAPO)的研究及HAPO的表型数据 随访研究(FUS)。Hapo显示，妊娠期高血糖，没有明显的糖尿病那么严重， 与产妇和新生儿不良结局风险增加独立相关。HAPO FUS 在出生后10-14年检查了HAPO母子对，以解决高血糖症的假设 在怀孕期间，没有明显的糖尿病严重，独立地与不良反应的风险增加有关。 儿童和母亲的结果。本研究的具体目的如下。(1)利用现有和 新的代谢组学数据用于确定孕期~28周的母体代谢物和代谢网络 与较高的新生儿和儿童期肥胖有关。关键代谢物的目标化验将是 开发用于量化其他HAPO母亲的代谢物水平，并验证已确定的关联。 (2)使用新的和现有的基因组数据来识别与关键基因水平相关的母体遗传变异 目标1中确定的代谢物，用于目标4中的预测模型。(3)解决以下假设 母体代谢物对胎儿肥胖症的影响是通过与胎儿基因的相互作用调节的：(A) 使用现有的胎儿GWAS数据来测试母体代谢物或代谢物网络之间的相互作用 胎儿基因在决定胎儿和儿童表型方面的作用；和(B)精细定位基因座在 调节母体代谢物或网络对胎儿和儿童表型的影响并建立 已确定的变体的功能后果。(4)使用母体表型、环境和遗传数据 与胎儿基因数据一起建立新生儿和儿童肥胖的预测模型。这些 研究将允许开发一个高新生儿和儿童的孕前预测模型。 肥胖症的长期目标是开发早期干预措施来改变子宫内脂肪积累的轨迹。

The prevalence of childhood obesity and related metabolic disorders is increasing. Early identification of offspring at risk for childhood obesity is critical to initiate early preventive interventions. Childhood obesity is determined by a complex mix of genetic and environmental factors. Important among these is the intrauterine environment as it impacts fetal adiposity, which our preliminary data show is highly associated with childhood adiposity. Thus, identifying factors important for fetal fat accretion a key challenge. We propose to address the hypothesis that maternal metabolites and metabolic networks during pregnancy impact newborn adiposity with varying degree depending upon the genetic susceptibility of the fetus and, ultimately, impact childhood adiposity and metabolic health. Our goal is to identify metabolites and metabolic pathways associated with fetal and childhood adiposity and determine whether these associations are impacted by fetal genetic variants. These data then will be used to develop a model for early prediction of fetal and childhood adiposity. We will accomplish this using phenotypic data, serum samples, and DNA from mothers and their offspring enrolled in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and phenotype data from the HAPO Follow-Up Study (FUS). HAPO showed that hyperglycemia in pregnancy, less severe than overt diabetes, is independently associated with increased risk of adverse maternal and neonatal outcomes. The HAPO FUS examined HAPO mother-child pairs ~10-14 years after delivery to address the hypothesis that hyperglycemia in pregnancy, less severe than overt diabetes, is independently associated with increased risk of adverse childhood and maternal outcomes. The specific aims for this study are as follows. (1) Leverage existing and new metabolomic data to identify maternal metabolites and metabolic networks at ~28 weeks gestation associated with higher newborn and childhood adiposity. Targeted assays for key metabolites will be developed to quantify metabolite levels in additional HAPO mothers and validate the identified associations. (2) Use new and existing genomic data to identify maternal genetic variation associated with levels of key metabolites identified in Aim 1 for use in predictive models in Aim 4. (3) Address the hypothesis that the impact of maternal metabolites on fetal adiposity is modulated through an interaction with fetal genotype by: (a) using existing fetal GWAS data to test for interaction between maternal metabolites or metabolite networks and fetal genotype in determining fetal and childhood phenotype; and (b) fine mapping genetic loci important in mediating the effect of maternal metabolites or networks on fetal and childhood phenotype and establishing the functional consequences of identified variants. (4) Use maternal phenotypic, environmental and genetic data together with fetal genetic data to establish predictive models for newborn and childhood adiposity. These studies will allow development of a model for pre-gestational prediction of higher newborn and childhood adiposity with a long-term goal of developing early interventions to alter the trajectory of in utero fat accretion.