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

MTNR1B 和 CRY2 变异对睡眠昼夜节律生理和代谢的影响

基本信息

批准号：
8139804
负责人：
RICHA SAXENA
金额：
$ 18.16万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139804
关键词：
Acute Affect Age Agonist Alleles Architecture Behavior Behavioral Biological Markers Body Temperature Cardiovascular Diseases Cardiovascular system Circadian Rhythms Clinical Cohort Studies Data Data Set Development Diabetes Mellitus Diagnosis Disease Enrollment Experimental Designs Fasting Future General Population Genes Genetic Risk Genetic Translation Genetic Variation Genotype Glucose Glycosylated hemoglobin A Hormones Individual Insulin Intervention Laboratories Laboratory Study Lead Link Measurement Measures Mediating Melatonin Melatonin Receptors Metabolic Metabolic Diseases Metabolism Non-Insulin-Dependent Diabetes Mellitus Outcome Pathway interactions Patient Self-Report Phenotype Physicians Physiological Physiology Play Polysomnography Population Population Heterogeneity Population Sizes Population Study Prevention Protocols documentation Questionnaires Receptor Gene Receptor, Melatonin, MT2 Regulation Relative (related person)Reporting Research Resources Risk Role Sampling Sleep Sleep Architecture Sleep Wake Cycle System Testing Therapeutic Therapeutic Studies Time Variant Weight Gain actigraphy base circadian pacemaker cryptochrome 2 diabetes mellitus genetics diabetes risk disorder risk epidemiologic data fasting glucose feeding field study follow-up genetic variant genome wide association study glucose metabolism insight insulin secretion intravenous glucose tolerance test novel population based public health relevance response shift work trait translational study

项目摘要

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.

描述（由申请人提供）：令人信服的流行病学数据表明，睡眠持续时间不足，睡眠质量损害和班次工作暴露每种情况增加了体重增加的风险，2型糖尿病（T2D）和心血管疾病。此外，对照实验室研究表明，在转移工作冲动葡萄糖代谢中，睡眠持续时间减少，睡眠破坏和昼夜节律典型典型。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，与糖尿病的定量性状相关的基因座> 15个基因座。但是，对于这些变体增加T2D风险的机制知之甚少。有趣的是，褪黑激素受体基因MTNR1B和核心昼夜节律时钟基因CRY2中的两个新发现的T2D风险变体位于褪黑激素受体基因中，提供了昼夜节律和睡眠途径在葡萄糖代谢中起关键作用的引人注目和融合支持。在此应用中，我们将利用来自流行病学和实验室生理学研究的现有表型数据，以研究MTNR1B和CRY2变体在睡眠和昼夜节律调节中的生理作用，从而揭示了这些变体会增加T2D风险的潜在机制。具体而言，我们将测试MTNR1B，CRY2和所有已知T2D变体是否与表型相关，以：a）睡眠生理； b）昼夜节律生理学； c）葡萄糖代谢。这些关系将在四个理想的受试者种群中进行检查，这些人群现有，独特的睡眠，昼夜节律和糖尿病表型数据，我们还可以进行基因型分析。这些数据集是互补的，因为它们包括不同大小的人群，睡眠深度不同，昼夜节律和葡萄糖代谢表型测量值，包括（1）一项大型队列研究（n = 6400），基于调查表和基于睡眠物理学的测量表（n = 6400）（n = 6400）（持续时间，质量和建筑），昼夜节律生理学的估计（睡眠/唤醒周期的时间）以及代谢功能；（2,3）两项基于人群的研究（n = 200，450）收集了基于睡眠时间和计时的调查表和基于行为的量度，以及代谢功能的衡量；（4）在整个强化实验室睡眠和昼夜节律方案中，研究了一个更精选的“深层型”受试者（n = 250）。该项目的结果将为通过基因型预先选择的人以及在不同环境/行为暴露和药理干预措施（例如褪黑激素激动剂）的背景下的翻译研究提供了未来研究的实验设计。这项应用和基于我们发现的后续研究应能够促进遗传发现的临床翻译，以增强T2D的预防，代谢疾病风险的生物标志物的鉴定以及T2D的新治疗方法。公共卫生相关性：睡眠持续时间，睡眠质量和转移工作与2型糖尿病的风险增加有关。该项目旨在确定2型糖尿病遗传风险变异的影响，尤其是在MTNR1B和CRY2基因中，对睡眠，昼夜节律和代谢生理学的影响，如大规模现场研究和大量实验室研究中所评估。这项研究将提供对昼夜节律，睡眠和代谢变化的机械见解，从而介导2型糖尿病风险增加。