Genetic Determinants of Weight Loss and Resolution of Co-Morbidities

减肥的遗传决定因素和合并症的解决

• 批准号: 8043357
• 负责人: Glenn S Gerhard
• 金额: $ 49.26万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043357
• 关键词: Accounting; Affect; Alleles; Body Weight; Body Weight decreased; Body mass index; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Caucasoid Race; Cholesterol; Clinical; Clinical Data; Comorbidity; Consent; DNA; Data; Diabetes Mellitus; Diagnostic; Diet; Dietary Intervention; Dyslipidemias; Ethnic Origin; Family; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Genotype; Goals; Hepatic; Heritability; Heterogeneity; High Density Lipoproteins; Homeostasis; Human; Hypertension; Hypertriglyceridemia; Individual; Learning; Least-Squares Analysis; Liver; Medical; Metabolic; Modality; Molecular; Molecular Genetics; Morbid Obesity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Patients; Play; Population; Prognostic Marker; RNA; Regression Analysis; Research; Resistance; Resolution; Risk; Role; Sampling; Sampling Studies; Severity of illness; Techniques; Testing; Time; Treatment outcome; Variant; Weight; bariatric surgery; base; burden of illness; cohort; disorder risk; effective therapy; genetic variant; genome wide association study; improved; mortality; novel; programs; trait; weight maintenance

DESCRIPTION (provided by applicant): Obesity, commonly defined as a body mass index (BMI) greater than 30 kg/m2, is associated with an increased risk for a number of metabolic derangements including type 2 diabetes mellitus (T2D), hypertension (HTN), dyslipidemia including hypertriglyceridemia (hiTRI) and low HDL levels (loHDL), as well as cardiovascular disease and overall mortality. Morbid obesity (BMI>40 kg/m2), which afflicts over 5% of the U.S. population, further increases disease burden and risk of mortality. Weight loss is effective at decreasing these risks, as well as ameliorating disease severity, thus reducing body weight in the morbidly obese is a major clinical goal. Currently available dietary and pharmacological modalities can produce small to moderate levels of weight loss, which can have significant impact on comorbidities, but are difficult to achieve or sustain in many patients. Bariatric surgery has thus emerged as a highly effective therapy for long-term weight loss in morbidly obese patients, and more recently as a surgical therapy for the potential cure of type 2 diabetes. However, the degree of weight loss and improvement in specific co-morbid conditions is variable. Our long-term objectives are to identify the molecular and genetic determinants of dietary and surgical weight loss in the morbidly obese, as well as the factors related to the resolution of co-morbid conditions. Based upon heritability and linkage studies, as well as genome wide association studies, genetic variation appears to play a strong role in obesity and related co-morbid conditions. Only a few of these genes/loci have been studied in the context of morbid obesity. Our primary hypothesis is that genetic variants confer resistance to weight loss therapies and inhibit weight-loss induced resolution of co-morbid conditions. To date, only small studies of a few candidate genes have been evaluated in diet and surgical weight loss. The specific goals of this proposal are to first identify common genetic variants associated with weight loss outcomes through genotyping "Metabochip" SNPs in individuals who have undergone a prudent hypocaloric weight loss program and Roux-en-Y gastric bypass surgery. We will then test for association between SNPs and weight loss outcomes. All trait-associated markers will be validated in independent cohorts. We will then identify rare genetic variants associated with weight loss outcomes by direct sequencing of selected candidate genes, as well as prioritized genes associated with Metabochip loci. Finally, we will identify genes whose expression levels are associated with weight loss outcomes through profiling hepatic gene expression in liver RNA and identify both common and rare variants associated with these genes. Completion of these aims will enhance our understanding of the molecular mechanisms underlying heterogeneity in weight loss outcomes following dietary and surgical interventions in the morbidly obese population. PUBLIC HEALTH RELEVANCE: Severely obese people suffer from many medical problems such as diabetes, high blood pressure, and high cholesterol. Losing weight can help these problems in some, but not all, people and those who try to lose weight through either diet or surgery often regain weight. Little is known about why this occurs. This study will determine whether genes affect how people lose weight and whether their medical problems improve. Identifying these factors may help guide which types of weight loss therapies should be performed in the extremely obese population.

描述（由申请人提供）：肥胖通常定义为体重指数 (BMI) 大于 30 kg/m2，与多种代谢紊乱的风险增加相关，包括 2 型糖尿病 (T2D)、高血压 (HTN) ）、血脂异常，包括高甘油三酯血症 (hiTRI) 和低 HDL 水平 (loHDL)，以及心血管疾病和总体死亡率。病态肥胖（BMI>40 kg/m2）困扰着超过 5% 的美国人口，进一步增加了疾病负担和死亡风险。减肥可以有效降低这些风险，并改善疾病的严重程度，因此减轻病态肥胖者的体重是一个主要的临床目标。目前可用的饮食和药物方式可以产生小到中度的体重减轻，这对合并症有显着影响，但对许多患者来说很难实现或维持。因此，减肥手术已成为病态肥胖患者长期减肥的高效疗法，最近又成为潜在治愈 2 型糖尿病的手术疗法。然而，特定合并症的体重减轻和改善程度是可变的。我们的长期目标是确定病态肥胖者饮食和手术减肥的分子和遗传决定因素，以及与共病缓解相关的因素。根据遗传性和连锁研究以及全基因组关联研究，遗传变异似乎在肥胖和相关共病中发挥着重要作用。在病态肥胖的背景下，仅研究了其中的少数基因/基因座。我们的主要假设是，遗传变异会导致对减肥疗法的抵抗，并抑制减肥引起的共病症状的缓解。迄今为止，仅对少数候选基因在饮食和手术减肥方面进行了小型研究评估。该提案的具体目标是首先通过对经历过谨慎的低热量减肥计划和 Roux-en-Y 胃绕道手术的个体进行“Metabochip”SNP 基因分型，识别与减肥结果相关的常见遗传变异。然后我们将测试 SNP 与减肥结果之间的关联。所有性状相关标记都将在独立队列中进行验证。然后，我们将通过对选定的候选基因以及与 Metabochip 基因座相关的优先基因进行直接测序来识别与减肥结果相关的罕见遗传变异。最后，我们将通过分析肝脏 RNA 中的肝脏基因表达来鉴定其表达水平与减肥结果相关的基因，并鉴定与这些基因相关的常见和罕见变异。完成这些目标将增强我们对病态肥胖人群饮食和手术干预后减肥结果异质性分子机制的理解。 公共健康相关性：严重肥胖者患有许多健康问题，如糖尿病、高血压和高胆固醇。减肥可以帮助某些人（但不是全部）解决这些问题，而那些尝试通过节食或手术减肥的人往往体重会反弹。人们对为什么会发生这种情况知之甚少。这项研究将确定基因是否影响人们的减肥方式以及他们的健康问题是否得到改善。识别这些因素可能有助于指导应在极度肥胖人群中进行哪种类型的减肥疗法。