HDHL DIMENSION: Dietary induced methylome and transcriptome dynamics assessing nutrition impacts on cardiovascular and metabolic health

心血管和代谢性疾病是全世界发病率和死亡率的主要原因。饮食是心脏代谢健康的主要风险因素，但研究具有挑战性，部分原因是对饮食的代谢反应高度个性化。确定调节对饮食的个性化反应的分子途径对于有效应对当前的流行病至关重要。表观遗传机制是基因功能的关键调节机制，可以随着包括饮食在内的外部刺激而改变。然而，对饮食反应的表观遗传动力学的纵向研究很少。我们的假设是，饮食诱导的表观遗传标记的识别与心脏代谢特征的表观遗传特征一起解释了饮食代谢反应的个体间变异性及其对健康的下游影响。维度联盟将通过动态调查饮食摄入对组织中基因功能的表观遗传调节的因果影响，以及它们对随后的心脏代谢健康结果的影响来检验这一假设。该提案将探索在餐后状态下食物摄入后立即发生的基因调控和功能途径，以及与习惯性饮食摄入有关的基因调控和功能途径。我们将测试在很大程度上被忽视的餐后代谢反应，尽管揭示了饮食诱导的代谢健康的多个方面，仅通过研究禁食状态是无法检测到这些方面的。此外，人类一生中的大部分时间都处于餐后血糖和血脂状态，这本身就是心血管疾病的独立风险因素。工作方案的基础是：(I)有针对性的餐后和营养干预研究，以处理饮食、表观遗传修饰和基因功能之间的因果关系，并结合(Ii)最先进的分析，以确定饮食、表观遗传和心脏代谢健康之间的联系，使用新的饮食措施，包括在广泛研究的队列中的代谢组学，以及(Iii)功能后续实验，评估饮食诱导的表观遗传和转录信号在细胞、组织内和组织间的影响。使用互补的方法，维度联盟将提供关于营养修改如何确切地调节调节和功能基因组以促进心脏代谢健康的新的机械性见解。这些见解将补充传统的以人口为基础的指导方针，并为迅速发展的基于营养的个性化战略领域提供信息。

Cardiovascular and metabolic diseases are a primary cause of morbidity and mortality worldwide. Diet is a major risk factor for cardio-metabolic health, but is challenging to study in part because metabolic response to diet is highly individualised. Characterising the molecular pathways that mediate personalised responses to diet is critical to effectively tackle the current epidemic. Epigenetic mechanisms are key regulators of gene function that can change in response to external stimuli, including diet. However, longitudinal studies of epigenetic dynamics in response to diet are rare. Our hypothesis is that the identification of dietary induced epigenetic marks together with epigenetic signatures of cardio-metabolic traits explain inter-individual variability in metabolic response to diet and its downstream effects on health. The DIMENSION consortium will test this hypothesis by investigating dynamically the causal impacts of dietary intake on epigenetic regulation of gene function across tissues, and their impact on subsequent cardio-metabolic health outcomes. The proposal will explore the gene regulatory and functional pathways that occur immediately following food intake in the postprandial state, as well as with habitual dietary intakes. We will test postprandial metabolic responses that have been largely overlooked, despite revealing multiple aspects of diet induced metabolic health that would not be detectable from studying fasting status alone. Further, humans spend the majority of their lives in the postprandial glycemic and lipemic state, which are themselves independent risk factors of cardiovascular disease. The work programme is based on: (i) targeted postprandial and nutritional intervention studies to tackle the causal relationships between diet, epigenetic modifications and gene function, in combination with (ii) state-of-the-art analyses to characterize the links between diet, epigenetics, and cardio-metabolic health using novel diet measures including metabolomics in extensively studied cohorts, and (iii) functional follow-up experiments assessing the impact of diet-induced epigenetic and transcriptomic signals at the level of cells, within and across tissues. Using complementary approaches, the DIMENSION consortium will deliver novel mechanistic insights into how exactly nutritional modifications can modulate the regulatory and functional genome to promote cardio-metabolic health. These insights will complement traditional population-based guidelines and inform the rapidly evolving area of individualised nutrition-based strategies.