Inter-generational Link of Cardio-Metabolic Risk: Integrate Multi-OMICs with Birth Cohort

摘要 超过一半的美国母亲在怀孕时超重或肥胖(Owo)； 母亲肥胖被认为是下一代肥胖风险的主要决定因素。 在母体高血压病之前和之前，观察到类似的代际联系 在怀孕期间。这种代际联系可能起源于子宫，并放大心脏- 当代和未来几代人的代谢风险。然而，问题仍然存在，即 潜在的机制是什么，以及可以做些什么来减轻孕产妇的不利影响 心脏代谢紊乱对子代健康的影响。 我们建议利用波士顿出生队列(BBC)的特殊资源，这是 美国最大和最长的高风险城市低收入少数族裔出生队列，以调查 心脏代谢结果的代际联系和母亲叶酸/B12营养的作用 (可改变的早期生命因素)，并探索看似合理的表观遗传学基础。此外， 通过将胎儿多组学数据(基因组、表观基因组和代谢组)与母体和 胎儿流行病学和临床数据，我们寻求更准确地描述新生儿的未来 21岁以下发生心脏代谢不良后果的风险。 我们的建议有很强的科学前提。动物模型和人体研究 暗示宫内期是建立表观遗传变异的关键时期。 表观遗传调控涉及一系列重要的生物学功能，包括 脂肪生成、葡萄糖动态平衡、炎症和胰岛素信号。因此，胎儿 表观遗传机制对于理解心脏代际联系至关重要。 代谢紊乱。然而，目前还没有足够的力量来预测出生队列。 评估胎儿表观基因组的作用的研究(使用最新的图谱技术)以及 母体叶酸/B12在美国人群代际心脏代谢风险中的地位。我们的 来自BBC的有希望的初步数据也支持这项提议，表明 母体叶酸状况影响子代DNA甲基化和心脏代谢结果 并减轻母体心脏代谢紊乱对后代健康的不利影响。 这项研究的成功完成将提高我们对代际关系的理解 心脏代谢风险，并导致早期预测和预防的新范式 扭转代际恶性循环，从关键的发展窗口期开始 干预措施可能在改善终身健康和减少健康方面产生最大影响 当代和未来几代人之间的差距。

Abstract More than half of U.S. mothers entered pregnancy with overweight or obesity (OWO); maternal obesity is considered a major determinant of the next generations' OWO risk.7 A similar inter-generational link was observed for maternal hypertensive disorders before and during pregnancy. This inter-generational link may originate in utero and amplify the cardio- metabolic risk in current and future generations. However, questions remain about what the underlying mechanisms are and what can be done to mitigate the adverse effects of maternal cardio-metabolic disorders on offspring health. We propose to leverage the exceptional resources of the Boston Birth Cohort (BBC), one of the largest and longest U.S. high-risk urban low-income minority birth cohorts, to investigate the inter-generational link of cardio-metabolic outcomes and the role of maternal folate/B12 nutrition (modifiable early life factors), and to explore plausible epigenetic underpinnings. Furthermore, by combining fetal multi-omics data (genome, epigenome, and metabolome) with maternal and fetal epidemiological and clinical data, we seek to more precisely characterize newborns' future risk for the development of adverse cardio-metabolic outcomes up to age 21 years. Our proposal has a strong scientific premise. Both animal models and human studies implicate the intrauterine period as a critical time for the establishment of epigenetic variability. Epigenetic regulation has been implicated in a range of important biological functions, including adipogenesis, glucose homeostasis, inflammation, and insulin signaling. As such, fetal epigenetic mechanisms are critical for understanding an inter-generational link of cardio- metabolic disorders. However, currently there is no adequately powered prospective birth cohort study to assess the role of the fetal epigenome (using the latest profiling technology) along with maternal folate/B12 status in inter-generational cardio-metabolic risk in U.S. populations. Our proposal is also supported by promising preliminary data from the BBC, indicating that maternal folate status influences offspring DNA methylation and cardio-metabolic outcomes and mitigates the adverse effects of maternal cardio-metabolic disorders on offspring health. Successful completion of this study will improve our understanding of inter-generational cardio-metabolic risk and lead to a new paradigm for early prediction and prevention to halt or reverse the vicious inter-generational cycle, beginning at critical developmental windows when interventions may have the greatest impact on improving life-long health and reducing health disparities in current and future generations.