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Genetic Epidemiology of Metabolic Diseases of Obesity

肥胖代谢性疾病的遗传流行病学

基本信息

批准号：
8068641
负责人：
Ingrid Bernadette Borecki
金额：
$ 54.87万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068641
关键词：
Abdomen Accounting African American Alcohol consumption Antioxidants Architecture Arteries Atherosclerosis Blood Pressure Caucasians Caucasoid Race Chromosome Mapping Coronary Coronary Arteriosclerosis Data Data Coordinating Center Data Set Databases Diabetes Mellitus Diet Dietary Factors Dietary Questionnaires Dietary intake Disease Environment Environmental Exposure Environmental Risk Factor Enzymes Epidemic Epidemiology Equation Exhibits Family Family Study Family member Fatty Liver Fatty acid glycerol esters Funding Genes Genetic Genetic Determinism Genetic Markers Genome Genomics Genotype Glucose Goals Head Health Heart Heritability Insulin Insulin Resistance Link Lipids Lipoproteins Liver Liver diseases Maps Measurement Measures Meta-Analysis Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Methods Microsatellite Repeats Modeling Multivariate Analysis National Heart, Lung, and Blood Institute Obesity Parents Participant Pathway interactions Patient Self-Report Pattern Phenotype Physical activity Prevalence Procedures Public Health Quantitative Trait Loci Questionnaires Race Reading Research Personnel Resources Risk Risk Factors Role Sampling Scanning Screening procedure Services Structure System Universities Unsaturated Fats Variant Visceral X-Ray Computed Tomography abdominal fat attenuation base biological systems calcification case control cost cost effective density epidemiological model family genetics forest gene discovery genetic analysis genetic epidemiology genetic linkage analysis genome wide association study genome-wide linkage inflammatory marker insight interest non-alcoholic fatty liver nonalcoholic steatohepatitis novel subcutaneous synergism trait

项目摘要

DESCRIPTION (provided by applicant): Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of metabolic syndrome (MetS) and non- alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, both of which are influenced by obesity and, specifically, increased stores of abdominal visceral fat and insulin resistance, are highly intertwined and have both genetic and environmental determinants. Characterization of fatty liver (steatosis) in conjunction with liver enzymes and abdominal fat depots in a large family study will provide an unprecedented opportunity to study the genetic epidemiology of MetS and NAFLD. Using existing CT scans obtained in over 3,300 Caucasian and African-American subjects from families of the NHLBI Family Heart Study (FHS), we propose to obtain measures of four focal phenotypes: liver attenuation, and total, subcutaneous, and visceral abdominal fat. Combined with the wealth of phenotypic and genetic information available already in the FHS, we will carry out studies of the genetic epidemiology of these important phenotypes, with the goal of identifying risk factors for these diseases including both genetic and environmental factors. We will use standard epidemiological models to characterize the risk factors for NAFLD, specifically, dietary factors (as ascertained using the Willett questionnaire), habitual physical activity, and alcohol consumption. Using existing measures of coronary and aortic artery calcification on these subjects, we will also characterize the influence of steatosis and abdominal fat on the degree of subclinical atherosclerosis. While the genetic basis of abdominal fat is well-established exhibiting a heritability of 50-70%, a recent study has estimated the heritability of liver attenuation to be 34%, suggesting that mapping studies are warranted. Genetic scans will be carried out in both Caucasian and African-American families using a panel of over 400 microsatellite linkage markers that are already typed on these subjects, to identify regions harboring trait loci. Genomewide association scans are being currently conducted for 1,000 Caucasian cases and controls for atherosclerosis, and for all 622 African-American subjects. These genotypes also will be available to this project to enhance the power for gene discovery and localization. Finally, we are particularly interested in characterizing the systems biological multivariate relationships among our focal phenotypes with other aspects of the MetS including insulin and glucose levels, insulin resistance, blood pressure, and lipids and lipoproteins in order to identify determinants that explain the clustering in this adverse risk factor profile. The proposed studies will help localize genes involved in the metabolic diseases of obesity, help elucidate the role of environmental exposures in these pathways, and will be among the largest, most definitive studies to date on fatty liver disease. Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of diabetes, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, all of which are influenced and exacerbated by obesity are highly intertwined and have both genetic and environmental determinants. The overall goal of this project is to study abdominal fat patterning and NAFLD, both of which are associated with insulin resistance, to identify their underlying genetic architecture using state of the art genome screening methods, evaluate the influence of diet and physical activity, and to understand their relationship to features of the MetS and coronary artery disease. PUBLIC HEALTH RELEVANCE: Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of diabetes, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, all of which are influenced and exacerbated by obesity are highly intertwined and have both genetic and environmental determinants. The overall goal of this project is to study abdominal fat patterning and NAFLD, both of which are associated with insulin resistance, to identify their underlying genetic architecture using state of the art genome screening methods, evaluate the influence of diet and physical activity, and to understand their relationship to features of the MetS and coronary artery disease.

描述（申请人提供）：肥胖已成为一种全国性的流行病。对健康的影响是多方面的，包括代谢综合征（MetS）和非酒精性脂肪性肝病（NAFLD）的风险和患病率的增加。这两种情况的代谢基础都受到肥胖的影响，特别是腹部内脏脂肪储存增加和胰岛素抵抗，这两种情况高度交织在一起，既有遗传因素，也有环境因素。在一项大型家庭研究中，脂肪肝（脂肪变性）与肝酶和腹部脂肪库的特征将为研究MetS和NAFLD的遗传流行病学提供前所未有的机会。利用现有的来自NHLBI家族心脏研究（FHS）家庭的3,300多名高加索人和非裔美国人的CT扫描，我们建议获得四种局灶表型的测量：肝脏衰减，总脂肪，皮下脂肪和内脏腹部脂肪。结合FHS中已有的丰富表型和遗传信息，我们将开展这些重要表型的遗传流行病学研究，目的是确定这些疾病的风险因素，包括遗传因素和环境因素。我们将使用标准的流行病学模型来描述NAFLD的危险因素，特别是饮食因素（通过Willett问卷确定）、习惯性体育活动和饮酒。利用现有的冠状动脉和主动脉钙化测量方法，我们还将描述脂肪变性和腹部脂肪对亚临床动脉粥样硬化程度的影响。虽然腹部脂肪的遗传基础已经确定，显示出50-70%的遗传率，但最近的一项研究估计，肝脏衰减的遗传率为34%，这表明进行图谱研究是有必要的。基因扫描将在白种人和非裔美国人家庭中进行，使用一个由400多个微卫星连锁标记组成的小组，这些标记已经在这些主题上键入，以确定包含特征位点的区域。目前正在对1000例白种人和动脉粥样硬化对照组以及所有622名非裔美国人进行全基因组关联扫描。这些基因型也将用于本项目，以增强基因发现和定位的能力。最后，我们特别感兴趣的是描述我们的病灶表型与MetS的其他方面（包括胰岛素和葡萄糖水平、胰岛素抵抗、血压、脂质和脂蛋白）之间的系统生物学多变量关系，以确定解释这一不利风险因素概况聚集的决定因素。拟议的研究将有助于定位与肥胖代谢疾病有关的基因，有助于阐明环境暴露在这些途径中的作用，并将成为迄今为止最大、最明确的脂肪肝疾病研究之一。肥胖已成为一种全国性的流行病。对健康的影响是多方面的，包括糖尿病、代谢综合征（MetS）和非酒精性脂肪性肝病（NAFLD）的风险和患病率增加。这些疾病的代谢基础都受到肥胖的影响和加剧，它们高度交织在一起，既有遗传因素，也有环境因素。该项目的总体目标是研究腹部脂肪模式和NAFLD，这两者都与胰岛素抵抗相关，利用最先进的基因组筛选方法确定其潜在的遗传结构，评估饮食和身体活动的影响，并了解它们与MetS和冠状动脉疾病特征的关系。公共卫生相关性：肥胖已成为一种全国性的流行病。对健康的影响是多方面的，包括糖尿病、代谢综合征（MetS）和非酒精性脂肪性肝病（NAFLD）的风险和患病率增加。这些疾病的代谢基础都受到肥胖的影响和加剧，它们高度交织在一起，既有遗传因素，也有环境因素。这个项目的总体目标是研究腹部脂肪模式和NAFLD，两者都与