Genetic Epidemiology of Metabolic Diseases of Obesity

描述（由申请人提供）：肥胖已成为一种全国性的流行病。健康后果是多方面的，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。这些疾病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，它们高度交织在一起，具有遗传和环境决定因素。在一项大型家族研究中，结合肝酶和腹部脂肪库对脂肪肝（脂肪变性）进行表征，将为研究MetS和NAFLD的遗传流行病学提供前所未有的机会。使用现有的CT扫描获得超过3,300名白人和非洲裔美国人的家庭的NHLBI家庭心脏研究（FHS）的主题，我们建议获得四个焦点表型的措施：肝脏衰减，和总，皮下，内脏腹部脂肪。结合FHS中已有的丰富的表型和遗传信息，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，包括遗传和环境因素。我们将使用标准流行病学模型来描述NAFLD的风险因素，特别是饮食因素（使用Willett问卷确定），习惯性体力活动和饮酒。利用这些受试者的冠状动脉和主动脉钙化的现有测量方法，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立，表现出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%，这表明映射研究是必要的。将在高加索人和非洲裔美国人家庭中进行基因扫描，使用一组400多个微卫星连锁标记，这些标记已经在这些受试者中定型，以确定携带性状基因座的区域。目前正在对1,000例高加索人动脉粥样硬化病例和对照组以及所有622例非洲裔美国人受试者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表征我们的焦点表型与其他方面的代谢综合征，包括胰岛素和葡萄糖水平，胰岛素抵抗，血压，脂质和脂蛋白，以确定决定因素，解释在这个不利的风险因素配置文件的集群系统的生物多变量关系。拟议的研究将有助于定位参与肥胖代谢疾病的基因，有助于阐明环境暴露在这些途径中的作用，并将成为迄今为止关于脂肪肝疾病的最大，最具权威性的研究之一。肥胖已成为一种全国性的流行病。健康后果是多方面的，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，所有这些都受到肥胖的影响和加剧，是高度交织在一起的，有遗传和环境决定因素。该项目的总体目标是研究腹部脂肪模式和NAFLD，两者都与胰岛素抵抗相关，使用最先进的基因组筛选方法确定其潜在的遗传结构，评估饮食和体力活动的影响，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流行病。健康后果是多方面的，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，所有这些都受到肥胖的影响和加剧，是高度交织在一起的，有遗传和环境决定因素。该项目的总体目标是研究腹部脂肪模式和NAFLD，两者都与 胰岛素抵抗，使用最先进的基因组筛选方法鉴定其潜在的遗传结构，评估饮食和体力活动的影响，并了解它们与MetS和冠状动脉疾病特征的关系。

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.