The Role of Circadian Periodicity in Human Cardiovascular Disease and Diabetes

描述（由申请人提供）：几条证据表明昼夜节律参与了人类疾病的发病机制。人类昼夜节律系统由中央起搏器（视交叉上核）和位于几乎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。褪黑激素是一种由松果体分泌的激素（在视交叉上核的控制下），并被带入明暗周期的黑暗阶段。除了作为抗氧化剂，褪黑激素抑制交感神经流出，促进血管舒张，并影响胰岛素分泌。作为生物钟的分子介质，褪黑素在前瞻性数据中与高血压的发展呈负相关，在横断面研究中与心血管疾病（CVD）的患病率呈负相关;此外，褪黑素受体的多态性与2型糖尿病（T2DM）相关。然而，褪黑激素的产生是否与未来的CVD事件和T2DM事件独立相关尚未研究。虽然人类遗传学研究表明，控制昼夜节律系统的核心基因的常见变异（例如，clock，arntl）可能影响T2DM和高血压的发展，与CVD的关联尚未报道，并且尚未探索昼夜节律紊乱（短睡眠持续时间、轮班工作、打鼾）与这些变体之间的潜在相互作用。最后，昼夜节律系统的元素之间的关系（即，褪黑激素、昼夜节律基因）和CVD/T2DM介导物之间的关系尚不清楚。我们将研究的3个主要假设是：（1）较低的褪黑激素产生与CVD有关（2）昼夜节律基因的常见变异与CVD和T2DM相关，并且这种相关性被昼夜节律破坏性因素改变;以及（3）较低的褪黑激素产生和昼夜节律基因变体都与炎症、胰岛素抵抗和内皮功能障碍有关。在这项研究中，我们建议借鉴新的数据收集和广泛的现有遗传数据，从正在进行的护士健康研究（NHS）队列。目的1将采用两个嵌套的病例对照研究（各400例病例对照对），以检查褪黑激素的产生与CVD和T2DM事件发生风险之间的前瞻性关联。目标2将采用一个大型子队列（N = 11，587）来研究昼夜节律控制基因中的常见遗传变异是否与普遍的CVD和T2DM相关，以及前瞻性地，这些变异是否与CVD和T2DM发展中的睡眠时间短，夜班轮班工作和打鼾相互作用。目标3将检查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的结果将有助于阐明昼夜节律失调与心血管疾病和2型糖尿病之间的关系，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.