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OWO风险的主要决定因素。 类似的代际联系被观察到母亲的高血压疾病之前， 孕期这种代际联系可能起源于子宫内，并放大了心脏- 代谢风险在当前和未来几代人。然而，问题仍然存在， 潜在的机制是什么，可以做些什么来减轻孕产妇的不利影响， 心脏代谢紊乱对后代健康的影响 我们建议利用波士顿出生队列（BBC）的特殊资源， 最大和最长的美国高风险城市低收入少数民族出生队列，调查 心脏代谢结果的代际联系和母亲叶酸/B12营养的作用 （可改变的早期生活因素），并探索合理的表观遗传基础。此外，委员会认为， 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岁以下发生不良心脏代谢结局的风险。 我们的建议有很强的科学前提。动物模型和人体研究 暗示子宫内时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、葡萄糖稳态、炎症和胰岛素信号传导。因此，胎儿 表观遗传机制对于理解心血管疾病的代际联系至关重要。 代谢紊乱然而，目前还没有充分把握度的前瞻性出生队列研究。 评估胎儿表观基因组作用的研究（使用最新的分析技术）沿着 母亲叶酸/B12状态在美国人群代际心脏代谢风险中的作用我们 英国广播公司的初步数据也支持这一提议，表明 母亲叶酸水平影响后代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。 成功完成这项研究将提高我们对代际关系的认识。 心脏代谢风险，并导致一个新的模式，为早期预测和预防，以停止或 扭转世代之间的恶性循环，从关键的发展窗口开始， 干预措施可能对改善终身健康和减少健康状况产生最大影响。 当前和未来几代人的差距。

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.