The Role of Circadian Periodicity in Human Cardiovascular Disease and Diabetes

描述（由申请人提供）：一些证据表明昼夜节律参与人类疾病的发病机制。人类的昼夜节律系统由一个中央起搏器（视交叉上核）和几乎位于每个人体组织中的外周振荡器组成，包括心脏、血管壁和胰腺的β细胞。褪黑素是由松果体（在视交叉上核的控制下）分泌的一种激素，被带入光-暗周期的暗期。褪黑素除了作为抗氧化剂外，还能抑制交感神经的分泌，促进血管松弛，影响胰岛素分泌。作为生物钟的分子介质，在前瞻性研究中，褪黑激素与高血压的发生呈负相关，在横断面研究中，褪黑激素与心血管疾病（CVD）的患病率呈负相关；此外，褪黑激素受体的多态性与2型糖尿病（T2DM）有关。然而，褪黑激素的产生是否与未来CVD事件和T2DM事件独立相关尚未研究。尽管人类遗传学研究表明，控制昼夜节律系统的核心基因（如时钟、arntl）的常见变异可能影响2型糖尿病和高血压的发展，但与心血管疾病的关联尚未报道，昼夜节律中断（短睡眠时间、轮流夜班工作、打鼾）与这些变异之间的潜在相互作用尚未探索。最后，昼夜节律系统元素（如褪黑激素、昼夜节律基因）与人类CVD/T2DM介质之间的关系尚不清楚。我们将研究的3个主要假设是：(1)褪黑素分泌降低与心血管疾病（心肌梗死[MI]和中风）和2型糖尿病有关；(2)昼夜节律基因的常见变异与CVD和T2DM相关，这种关联被昼夜节律干扰因素所改变；(3)褪黑激素分泌减少和昼夜节律基因变异都与炎症、胰岛素抵抗和内皮功能障碍有关。在这项研究中，我们建议利用正在进行的护士健康研究（NHS）队列的新数据收集和广泛的现有遗传数据。目的1将采用两组嵌套病例对照研究（每组400对病例对照研究）来研究褪黑素生成与心血管疾病和2型糖尿病事件发生风险之间的潜在关联。目的2将采用一个大型亚队列（N= 11587）来研究昼夜节律控制基因的常见遗传变异是否与CVD和T2DM的流行相关，并前瞻性地研究这些变异是否与睡眠时间短、轮流夜班工作和打鼾在CVD和T2DM的发展中相互作用。目的3将研究昼夜节律系统的元素（褪黑激素、遗传变异）是否与炎症、胰岛素抵抗和内皮功能障碍有关。这项高效且具有成本效益的研究结果将有助于阐明昼夜节律失调与CVD和T2DM之间的关系，并最终有助于确定新的治疗和预防策略。

DESCRIPTION (provided by applicant): Several lines of evidence point toward circadian involvement in the pathogenesis of human disease. The human circadian system consists of a central pacemaker (suprachiasmatic nucleus) and also peripheral oscillators that are located in nearly every human tissue, including the heart, vessel walls and beta cells of the pancreas. Melatonin is a hormone secreted by the pineal gland (under the control of the suprachiasmatic nucleus) and entrained to the dark phase of a light-dark cycle. Besides serving as an antioxidant, melatonin suppresses sympathetic outflow, promotes vascular relaxation, and affects insulin secretion. As a molecular mediator of the circadian clock, melatonin is inversely associated with the development of hypertension in prospective data, and inversely associated with the prevalence of cardiovascular disease (CVD) in cross- sectional studies; furthermore, polymorphisms in the melatonin receptors are associated with type 2 diabetes mellitus (T2DM). Whether melatonin production is independently associated with future CVD events and incident T2DM, however, has not been studied. Although human genetic studies suggest that common variants in core genes that control the circadian system (e.g., clock, arntl) may influence the development of T2DM and hypertension, associations with CVD have not been reported, and potential interactions between circadian disruption (short sleep duration, rotating night shift work, snoring) and these variants have not been explored. Finally, the relation between elements of the circadian system (i.e., melatonin, circadian genes) and CVD/T2DM mediators in humans is not well understood. The 3 major hypotheses that we will investigate are: (1) lower melatonin production is associated with CVD (myocardial infarction [MI] and stroke) and T2DM; (2) common variants in circadian genes are associated with CVD and T2DM, and the association is modified by circadian-disruptive factors; and (3) both lower melatonin production and circadian gene variants are associated with inflammation, insulin resistance, and endothelial dysfunction. In this study, we propose to draw on both new data collection and extensive existing genetic data from the ongoing Nurses' Health Study (NHS) cohort. Aim 1 will employ two nested case-control studies (400 case-control pairs each) to examine the prospective association between melatonin production and the risk of incident CVD and T2DM events. Aim 2 will employ a large sub-cohort (N=11,587) to investigate whether common genetic variants in circadian control genes are associated with prevalent CVD and T2DM, and prospectively, whether these variants interact with short sleep duration, rotating night shift work, and snoring in the development of CVD and T2DM. Aim 3 will examine whether elements of the circadian system (melatonin, genetic variants) are associated with inflammation, insulin resistance, and endothelial dysfunction. The results from this highly efficient and cost- effective study will help elucidate the relation between circadian misalignment and CVD and T2DM, and ultimately, could help identify novel treatment and prevention strategies.