Genetic Epidemiology of Metabolic Diseases of Obesity

描述(申请人提供)：肥胖已成为全国性的流行病。对健康的影响是多方面的，包括增加代谢综合征(METS)和非酒精性脂肪性肝病(NAFLD)的风险和患病率。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，这些因素高度交织在一起，既有遗传决定因素，也有环境决定因素。在一项大型家族研究中，脂肪肝(脂肪变性)的特征与肝酶和腹部脂肪堆积相结合，将为研究蛋氨酸和非酒精性脂肪肝的遗传流行病学提供前所未有的机会。利用来自NHLBI家庭心脏研究(FHS)家庭的3300多名高加索和非裔美国人受试者的现有CT扫描，我们建议获得四种局部表型的测量：肝脏衰减，以及腹部总脂肪、皮下脂肪和内脏脂肪。结合FHS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)、习惯性体力活动和饮酒。利用这些受试者冠状动脉和主动脉钙化的现有测量方法，我们还将表征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，遗传率为50%-70%，但最近的一项研究估计，肝脏衰减率的遗传率为34%，这表明有必要进行图谱研究。基因扫描将在高加索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受试者身上打印出来，以识别含有性状基因座的区域。目前正在对1000例高加索患者和动脉粥样硬化对照以及所有622名非裔美国人进行全基因组关联扫描。这些基因类型也将用于该项目，以增强基因发现和定位的能力。最后，我们特别感兴趣的是系统的生物学多变量关系的特征，我们的焦点表型与蛋氨酸代谢综合征的其他方面，包括胰岛素和血糖水平，胰岛素抵抗，血压，血脂和脂蛋白，以确定决定因素，以解释聚集在这一不利的风险因素概况。拟议中的研究将有助于定位与肥胖代谢性疾病有关的基因，有助于阐明环境暴露在这些途径中的作用，并将是迄今为止关于脂肪肝疾病的最大、最具权威性的研究之一。肥胖已经成为一种全国性的流行病。其健康后果是多方面的，包括增加糖尿病、代谢综合征(METS)和非酒精性脂肪性肝病(NAFLD)的风险和患病率。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，既有遗传决定因素，也有环境决定因素。该项目的总体目标是研究与胰岛素抵抗相关的腹部脂肪模式和NAFLD，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，并了解它们与蛋氨酸和冠状动脉疾病特征的关系。与公共健康相关：肥胖已经成为一种全国性的流行病。其健康后果是多方面的，包括增加糖尿病、代谢综合征(METS)和非酒精性脂肪性肝病(NAFLD)的风险和患病率。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，既有遗传决定因素，也有环境决定因素。这个项目的总体目标是研究腹部脂肪模式和非酒精性脂肪肝，两者都与 胰岛素抵抗，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，并了解它们与蛋氨酸代谢综合征和冠状动脉疾病的特征的关系。

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.