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、睡眠质量受损和轮班工作暴露均会增加体重增加、2型糖尿病（T2 D）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，昼夜节律紊乱-典型的轮班工作-损害葡萄糖代谢。最近的全基因组关联研究已经确定了>20个与T2 D相关的基因座和>15个与糖尿病数量性状相关的基因座。然而，关于这些变异增加T2 D风险的机制知之甚少。有趣的是，两个新发现的T2 D风险变体位于褪黑激素受体基因MTNR 1B和核心生物钟基因MTNR 2中，这为昼夜节律和睡眠途径在葡萄糖代谢中发挥关键作用提供了令人信服的支持。在本申请中，我们将利用流行病学和实验室生理学研究中现有的表型数据，研究MTNR 1B和MTNR 2变体在睡眠和昼夜节律调节中的生理作用，从而揭示这些变体增加T2 D风险的潜在机制。具体而言，我们将测试MTNR 1 B、MTNR 2和所有已知的T2 D变体是否与以下表型相关：a）睡眠生理学; B）昼夜生理学;和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查，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，我们还可以在其中进行基因型分析。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，并且包括（1）大型队列研究（n=6400），其中基于问卷和多导睡眠图的睡眠生理学测量结果包括（2）睡眠生理学测量结果。（持续时间，质量和结构），昼夜生理学的估计（睡眠/觉醒周期的时间）和代谢功能;（2，3）两项不同人群的研究（n=200，450）收集了问卷和基于活动记录的睡眠时间和时间测量以及代谢功能测量;和（4）在整个实验室内密集的睡眠和昼夜节律方案中研究的更多选择的和“深度表型化的”受试者群体（n=250）。该项目的结果将为未来研究的实验设计提供信息，这些研究是通过基因型预先选择的人，以及在不同环境/行为暴露和药物干预（例如褪黑激素激动剂）背景下的转化研究。这项应用和基于我们研究结果的后续研究将使遗传发现的临床转化成为可能，以加强T2 D的预防，识别代谢性疾病风险的生物标志物，以及T2 D的新治疗方法。 公共卫生相关性：睡眠时间，睡眠质量和轮班工作与2型糖尿病风险增加有关。该项目旨在确定2型糖尿病遗传风险变异的影响，特别是在MTNR 1B和MTNR 2基因中，对睡眠，昼夜节律和代谢生理学的影响，如在大规模实地研究和密集的实验室研究中评估的那样。这项研究将为昼夜节律，睡眠和代谢变化提供机制性见解，这些变化介导2型糖尿病风险增加。

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.