Impact of MTNR1B and CRY2 variants on sleep circadian physiology and metabolism

描述(由申请人提供)：令人信服的流行病学数据表明，睡眠时间不足、睡眠质量下降和轮班工作暴露都会增加体重增加、2型糖尿病(T2D)和心血管疾病的风险。此外，对照实验室研究表明，睡眠时间减少、睡眠中断和昼夜节律失调--这在倒班工作中很常见--会损害葡萄糖代谢。最近的全基因组关联研究已经确定了与T2D相关的20个基因座和与糖尿病数量性状相关的&gt；15个基因座。然而，人们对这些变异增加T2D风险的机制知之甚少。有趣的是，两个新发现的T2D风险变异体位于褪黑素受体基因MTNR1B和核心生物钟基因CRY2中，为昼夜节律和睡眠通路在葡萄糖代谢中发挥关键作用提供了引人注目的和集中的支持。在这项应用中，我们将利用现有的流行病学和实验室生理学研究的表型数据来研究MTNR1B和CRY2变异在睡眠和昼夜调节中的生理作用，从而揭示这些变异增加T2D风险的潜在机制。具体地说，我们将测试MTNR1B、CRY2和所有已知的T2D变体是否与以下表型相关：a)睡眠生理学；b)昼夜生理学；c)葡萄糖代谢。这些关系将在四个理想的受试者群体中进行检验，这些受试者群体具有现有的、独特的睡眠、昼夜节律和糖尿病表型数据，在这些数据中，我们还可以进行基因分型分析。这些数据集是互补的，因为它们包括具有不同睡眠深度、昼夜节律和葡萄糖代谢表型测量的不同规模的人群，并包括(1)一项大型队列研究(n=6400)，其中收集了基于问卷和多导睡眠图的睡眠生理学(持续时间、质量和结构)的测量，对昼夜生理学(睡眠/醒来周期的时间)和代谢功能的估计；(2，3)两项不同的基于人群的研究(n=200,450)，收集了问卷和基于活动的睡眠持续时间和计时的测量，以及代谢功能的测量；以及(4)在整个实验室密集睡眠和昼夜节律(n=250)中被研究的更精选和更深表型的受试者群体。该项目的结果将为未来对按基因预先选择的人进行的研究以及在不同环境/行为暴露和药物干预(例如褪黑素激动剂)背景下的翻译研究的实验设计提供参考。这项应用和基于我们发现的后续研究应该能够将基因发现转化为临床，以加强T2D的预防，识别代谢性疾病风险的生物标记物，以及T2D的新治疗方法。 公共卫生相关性：睡眠时间、睡眠质量和倒班工作与2型糖尿病风险增加相关。该项目旨在通过大规模实地研究和密集的实验室研究，确定2型糖尿病遗传风险变异，特别是MTNR1B和CRY2基因对睡眠、昼夜节律和代谢生理学的影响。这项研究将为调节2型糖尿病风险增加的昼夜节律、睡眠和新陈代谢变化提供机械性见解。

DESCRIPTION (provided by applicant): Convincing epidemiologic data indicate that inadequate sleep duration, compromised sleep quality and shift work exposure each increase the risk for weight gain, type 2 diabetes (T2D), and cardiovascular disease. In addition, controlled laboratory studies show that reduced sleep duration, sleep disruption, and circadian misalignment-typical in shift work-impair glucose metabolism. Recent genome-wide association studies have identified >20 loci associated with T2D and >15 loci associated with quantitative traits of diabetes. However, very little is known about the mechanisms by which these variants increase risk of T2D. Interestingly, two newly discovered T2D risk variants are located in the melatonin receptor gene MTNR1B and in the core circadian clock gene CRY2, providing compelling and converging support that circadian and sleep pathways play a key role in glucose metabolism. In this application, we will take advantage of existing phenotype data from epidemiologic and in-laboratory physiologic studies to investigate the physiological role of MTNR1B and CRY2 variants in sleep and circadian regulation, thereby revealing potential mechanisms by which these variants increase risk of T2D. Specifically, we will test whether MTNR1B, CRY2, and all known T2D variants are associated with phenotypes for: a) sleep physiology; b) circadian physiology; and c) glucose metabolism. These relationships will be examined in four ideal subject populations with existing, unique sleep, circadian and diabetes phenotype data in which we can also perform genotypic analysis. These data sets are complementary as they include varying sized populations with varying depth of sleep, circadian and glucose metabolism phenotypic measurements, and include (1) a large cohort study (n=6400) in which questionnaire and polysomnography-based measures of sleep physiology (duration, quality, and architecture), estimates of circadian physiology (timing of the sleep/wake cycle), and metabolic function were collected; (2,3) two diverse population-based studies (n=200, 450) that collected questionnaire and actigraphy-based measures of sleep duration and timing, and measures of metabolic function; and (4) a more selected and 'deeply-phenotyped' subject population studied throughout intensive in- laboratory sleep and circadian protocols (n=250). Results from this project will inform the experimental design of future studies in people pre-selected by genotype, as well as translational studies in the context of different environmental/behavioral exposures and pharmacological interventions (e.g. melatonin agonists). This application and the follow-up studies based on our findings should enable clinical translation of genetic discoveries for enhancing the prevention of T2D, identification of biomarkers for metabolic disease risks, and novel treatments of T2D. PUBLIC HEALTH RELEVANCE: Sleep duration, sleep quality and shift work are associated with an increased risk of type 2 diabetes. This project aims to determine the effect of type 2 diabetes genetic risk variants, particularly in the MTNR1B and CRY2 genes, on sleep, circadian and metabolic physiology as assessed in large-scale field studies and intensive in- laboratory studies. This research will provide mechanistic insights into circadian, sleep and metabolic changes that mediate increased risk of type 2 diabetes.