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——轮班工作中典型的现象——会损害葡萄糖代谢。最近的全基因组关联研究已经确定bbb20位点与T2D相关，>5位点与糖尿病的数量性状相关。然而，对于这些变异增加T2D风险的机制知之甚少。有趣的是，两个新发现的T2D风险变异位于褪黑激素受体基因MTNR1B和核心生物钟基因CRY2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和趋同的支持。在这项应用中，我们将利用流行病学和实验室生理学研究的现有表型数据来研究MTNR1B和CRY2变异在睡眠和昼夜节律调节中的生理作用，从而揭示这些变异增加T2D风险的潜在机制。具体来说，我们将测试MTNR1B、CRY2和所有已知的T2D变异是否与以下表型相关：a)睡眠生理学；B)昼夜生理；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，这些人群具有现有的，独特的睡眠，昼夜节律和糖尿病表型数据，我们也可以进行基因型分析。这些数据集是互补的，因为它们包括不同规模的人群，不同的睡眠深度，昼夜节律和葡萄糖代谢表型测量，并包括：(1)一项大型队列研究（n=6400），其中收集了基于问卷调查和多导睡眠图的睡眠生理学测量（持续时间，质量和结构），昼夜节律生理学估计（睡眠/觉醒周期的时间）和代谢功能；（2,3）两项不同的基于人群的研究（n= 200,450），收集了问卷调查和基于活动仪的睡眠持续时间和时间测量，以及代谢功能测量；(4)通过密集的实验室睡眠和昼夜节律方案（n=250）研究了一个经过更多选择和“深度表型”的受试者群体。该项目的结果将为未来研究的实验设计提供信息，这些研究是根据基因型预先选择的人群，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）的背景下进行的转化研究。这一应用和基于我们研究结果的后续研究应该能够使遗传学发现的临床转化，以加强T2D的预防，识别代谢疾病风险的生物标志物，以及T2D的新治疗方法。

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.