Pharmacogenetics of obesity and endocannabinergic modulation (POEM)

肥胖和内源性大麻素能调节的药物遗传学（POEM）

• 批准号: 7898850
• 负责人: Russell A. Wilke
• 金额: $ 33.61万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898850
• 关键词: Acute; Adipose tissue; Adult; Age; Alleles; Amidohydrolases; Anatomic Sites; Animals; Behavioral; Behavioral Genetics; Body Composition; Body fat; Body mass index; CNR1 gene; Candidate Disease Gene; Cannabis; Canned Foods; Centers for Disease Control and Prevention (U.S.); Central obesity; Cholesterol; Clinic; Clinical; Code; Cohort Studies; Communities; Comorbidity; Complex; DEXA; DNA; DNA Resequencing; Data; Databases; Density Gradient Centrifugation; Development; Disease; Dyslipidemias; Eating; Effectiveness; Endocannabinoids; Environmental Risk Factor; Enzymes; Epidemic; Etiology; European; Extended Family; Family; Fasting; Fatty acid glycerol esters; Food; Frequencies; Future; Gender; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glucose; Goals; Haplotypes; Health; Healthcare; High Density Lipoprotein Cholesterol; Hip region structure; Homeostasis; Human; Hydrolase Gene; Hypertriglyceridemia; Hypothalamic structure; Individual; Insulin; Insulin Resistance; International; Intravenous; Islets of Langerhans; Kinetics; LDL Cholesterol Lipoproteins; Laboratories; Leptin; Life; Ligands; Lipids; Lipoproteins; Liver; Maps; Measures; Medical; Medicine; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Midbrain structure; Modeling; Monoacylglycerol Lipases; Mutation; Names; Nucleotides; Obesity; Overweight; Particle Size; Pathway interactions; Patients; Peripheral; Pharmacogenetics; Phenotype; Population; Prevalence; Probability; Property; Receptor Gene; Receptor Signaling; Regulation; Research; Research Infrastructure; Research Project Grants; Rewards; Risk; Risk Factors; Role; Satiation; Scanning; Series; Serine; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Single Nucleotide Polymorphism; Site; Skeletal Muscle; Skinfold Thickness; Statistical Methods; Stimulus; Stratification; Study Subject; System; Testing; Transacylase; Triglycerides; United States; Validation; Variant; Visceral; Waist-Hip Ratio; Weight Gain; Wisconsin; X-Ray Computed Tomography; Yang; amidase; anandamide; base; biobank; blood glucose regulation; cannabinoid receptor; cohort; design; experience; fasting glucose; fatty acid amide hydrolase; food consumption; genetic analysis; glycemic control; human data; improved; in vivo; increased appetite; indexing; insulin sensitivity; interest; lipid disorder; obesity prevention; pleiotropism; population based; preclinical study; programs; public health relevance; response; subcutaneous; therapy design; trait; waist circumference

DESCRIPTION (provided by applicant): One of the most interesting cellular signaling pathways involved in the development of obesity and obesity-related comorbidity has been the endocannabinoid (eCB) system. It has been known for thousands of years that cannabis extracts increase appetite, particularly for highly palatable foods and can result in weight gain. The eCB system consists of two endogenous cannabinoid receptors, CB1 and CB2. Emerging animal and human data support the hypotheses that obesity and obesity-related metabolic disorders are associated with overactive signaling specifically at the level of the CB1 receptor (gene name CNR1). The CB1 receptor has two endogenous ligands: N-arachidonylethanolamine (AEA) and 2-arachdionylglycerol (2-AG). Synthesis of these ligands is regulated by a series of transacylases and phopholipases. Degradation of AEA is catalyzed by a serine amidase, fatty acid amide hydrolase (gene name FAAH). While 2-AG is degraded by multiple enzymes, recent evidence suggests a primary role for monoacylglycerol lipase (gene name MGLL). eCB/CB1 receptor signaling is involved in the regulation of food consumption and metabolism via multiple mechanisms: it regulates the rewarding properties of food via effects on central mesolimbic pathways; it also regulates food intake at the hypothalamus; and it modulates peripheral metabolism through effects on adipose tissue, the liver, skeletal muscle and the endocrine pancreas. Over-activity of eCB/CB1 signaling at any or all of these sites can result in increased food intake and/or altered metabolism, thus promoting obesity. The goal of the studies outlined in this application will be to define the degree to which eCB/CB1 signaling pathway gene variability contributes to human obesity. We propose to test this hypothesis in two independent study cohorts. Using haplotype tagging SNPs (tagSNPs) selected from the International Human Haplotype Map (HapMap), we have begun genotyping three critical eCB/CB1 signaling genes, and testing for association between variation in these candidate genes and obesity and obesity-related metabolic disorders (changes in insulin responsiveness and derangements in lipid homeostasis) in 2209 study subjects from 507 families participating in the Take Off Pounds Sensibly (TOPS) obesity research program. We plan to test tagSNPs in each of these candidate eCB/CB1 signaling genes for association with 12 quantitative traits: body mass index (BMI), waist circumference, hip circumference, waist/hip ratio (WHR), fasting glucose, insulin, insulin/glucose ratio, homeostasis model assessment of insulin resistance (HOMA-IR), fasting triglyceride levels, total cholesterol, LDL cholesterol, and HDL cholesterol. Any tagSNPs found to be associated with BMI (as a global measure of obesity) or WHR (as a measure of abdominal obesity) will be further tested for association with total body fat by DEXA scan (as a confirmatory measure of global obesity) and the ratio of visceral fat / subcutaneous fat by CT scan (as a confirmatory measure of abdominal obesity) in 504 rigorously phenotyped individuals from the 50 TOPS families that have proven most informative in prior genetic analyses. These 504 rigorously phenotyped individuals are nested within the original cohort. Any tagSNPs found to be associated with glucose homeostasis in the original cohort will also be tested for a relationship with insulin sensitivity in these 504 more rigorously phenotyped individuals using the minimal model (MinMod), which compensates for subject-to-subject variability in insulin and glucose kinetics. The MinMod provides four well characterized glycemic control parameters: insulin sensitivity (SI), acute insulin response to intravenous glucose (AIRG), glucose effectiveness (SG), and disposition index (DI). TagSNPs found to be associated with lipid levels in the original cohort will also be tested for association with lipoprotein particle size distribution in these 504 subjects. All three candidate genes (FAAH, MGLL, and CNR1) will then be resequenced in 96 obese study subjects with insulin resistance and dyslipidemia identified from within the original TOPS cohort. All common and rare variants will be re-genotyped in the entire cohort (n = 2209), and Bayesian statistical methods will be employed to identify potentially causative alleles. For each gene, causative polymorphisms will be prioritized using a quantitative trait nucleotide (QTN) approach, and all variants with greater than 80% posterior probability of effect (based upon Bayesian information criterion) will be genotyped in a second population, the Marshfield Clinic Personalized Medicine Research Project (PMRP). The PMRP database represents one of the largest population-based Biobanks in the U.S (n = 19,573). This cohort will allow us to test the generalizability of our initial findings a population of similar ethnic composition. Each variant from the original family-based cohort will be prioritized according to pleiotropy (i.e., association with more than one obesity-related phenotypic trait). We will then use the PMRP population to test the most informative obesity alleles for association with BMI, and the most informative metabolic alleles for association with fasting glucose and routine clinical lipid data. PUBLIC HEALTH RELEVANCE: The current obesity epidemic represents a major international health crisis. The prevalence of obesity-related medical problems is continuing to increase, placing an unprecedented burden on health care infrastructure. We plan to quantify the role of three candidate genes in the development of obesity and obesity-related medical problems. In the future, individual patients with variation in these genes may benefit from targeted behavioral and/or pharmacological interventions designed to improve their health.

描述（由申请人提供）：肥胖和与肥胖相关的合并症所涉及的最有趣的细胞信号通路之一是内源性大麻素（ECB）系统。数千年来，大麻提取物增加了食欲，尤其是对于高度可口的食物，可能导致体重增加。欧洲央行系统由两个内源性大麻素受体CB1和CB2组成。新兴的动物和人类数据支持肥胖和与肥胖相关的代谢性疾病的假设与CB1受体水平（Gene Name CNR1）的水平特别活动相关。 CB1受体具有两个内源配体：N-芳基甲二氨基氨基胺（AEA）和2-芳基丁基甘油（2-AG）。这些配体的合成受一系列的跨环酶和哲学酶调节。 AEA的降解是由丝氨酸酰胺酶，脂肪酸酰胺水解酶（基因名称FAAH）催化的。尽管2-AG被多种酶降解，但最近的证据表明单酰基甘油脂肪酶（基因名称MGLL）的主要作用。 ECB/CB1受体信号通过多种机制涉及食物消耗和代谢的调节：它通过对中央中间途径的影响来调节食物的奖励性能；它还调节下丘脑的食物摄入量；它通过对脂肪组织，肝脏，骨骼肌和内分泌胰腺的影响来调节外周代谢。欧洲央行/CB1信号在任何或所有这些位点的过度活跃都会导致食物摄入量增加和/或代谢改变，从而促进肥胖症。本应用中概述的研究的目的是定义欧洲央行/CB1信号通路基因变异性有助于人类肥胖的程度。我们建议在两个独立的研究队列中检验这一假设。 Using haplotype tagging SNPs (tagSNPs) selected from the International Human Haplotype Map (HapMap), we have begun genotyping three critical eCB/CB1 signaling genes, and testing for association between variation in these candidate genes and obesity and obesity-related metabolic disorders (changes in insulin responsiveness and derangements in lipid homeostasis) in 2209 study subjects from 507 families participating在肥胖研究计划中明智地（顶部）脱掉体重。我们计划在这些候选ECB/CB1信号基因中测试与12个定量性状相关的TAGSNP：体重指数（BMI），腰围，臀部周长，腰围/髋关节比率（WHR），禁食葡萄糖，葡萄糖，胰岛素，胰岛素/葡萄糖比率，胰岛素/胰岛素模型，胰岛素模型的总体含量，胰岛素的限制，胰岛素的限制，含量，胰岛素量，含量，胰岛素量，含量，胰岛素量。胆固醇，LDL胆固醇和HDL胆固醇。任何发现与BMI（作为肥胖的全球量度）或WHR（作为腹部肥胖的量度）相关的任何TAGSNP，将进一步测试与DexA扫描（作为全球肥胖的确认性量度）与总体脂肪相关联（作为全球肥胖的确认性量），并且通过CT扫描量的持续性脂肪（作为次数的个体量）504的次数衡量量的肥胖量（504）在先前的遗传分析中证明最有用的家庭。这些504个严格的表型个体嵌套在原始队列中。在原始队列中发现与葡萄糖稳态相关的任何TAGSNP还将测试与使用最小模型（MINMOD）更严格地表型个体的胰岛素敏感性的关系，以补偿胰岛素和葡萄糖动力学的受试者对受试者的变化。 MINMOD提供了四个表征良好的血糖控制参数：胰岛素敏感性（SI），急性胰岛素对静脉葡萄糖（AIRG），葡萄糖有效性（SG）和处置指数（DI）的反应。在原始队列中发现与脂质水平相关的TAGSNP也将与这504名受试者中的脂蛋白粒度分布相关。然后，所有三个候选基因（FAAH，MGLL和CNR1）将在96名肥胖研究受试者中重新公平，并从原始顶部组中鉴定出胰岛素抵抗和血脂异常。所有常见和罕见的变体将在整个队列中重新分类（n = 2209），并将采用贝叶斯统计方法来识别潜在的导致等位基因。对于每个基因，将使用定量性状核苷酸（QTN）方法优先考虑致命多态性，并且所有具有大于80％后验效率的变体（基于贝叶斯信息标准）将在第二个人群中基因分型，第二个人群，Marshfield诊所诊所诊所研究项目（PMRP）。 PMRP数据库代表了美国最大的基于人群的生物库之一（n = 19,573）。该队列将使我们能够测试初始发现的普遍性，具有相似的种族组成。原始基于家庭的队列的每个变体将根据多效性（即与多个与肥胖相关的表型性状相关联）优先考虑。然后，我们将使用PMRP种群测试与BMI关联的最有用的肥胖等位基因，以及与禁食葡萄糖和常规临床脂质数据相关的最有用的代谢等位基因。公共卫生相关性：当前的肥胖症流行代表了一次重大的国际健康危机。与肥胖相关的医疗问题的患病率正在继续增加，这给医疗保健基础设施带来了前所未有的负担。我们计划量化三个候选基因在肥胖和与肥胖相关的医学问题发展中的作用。将来，这些基因变异的个别患者可能会受益于旨在改善其健康的靶向行为和/或药理干预措施。