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: 8435451
• 负责人: Glenn S Gerhard
• 金额: $ 49.67万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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/8435451
• 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; public health relevance; 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.

描述（由申请人提供）：肥胖，通常定义为大于30 kg/m2的体重指数（BMI），与许多代谢疾病（包括2型糖尿病）的风险增加有关心血管疾病和整体死亡率。折磨超过5％的美国人群的病态肥胖（BMI> 40 kg/m2）进一步增加了疾病负担和死亡率。体重减轻可有效地降低这些风险，并改善疾病的严重程度，因此减轻病态肥胖的体重是一个主要的临床目标。目前可用的饮食和药理方式可能会产生较小至中等水平的体重减轻，这可能会对合并症产生重大影响，但在许多患者中很难实现或维持。因此，减肥手术已成为病态肥胖患者长期体重减轻的一种高效治疗，最近作为一种潜在治疗2型糖尿病的手术疗法。但是，特定合并条件的体重减轻程度和改善是可变的。我们的长期目标是确定病态肥胖的饮食和手术体重减轻的分子和遗传决定因素，以及与解决合并症条件有关的因素。基于遗传力和联系研究以及基因组广泛的关联研究，遗传变异似乎在肥胖症和相关的合并症中起着重要作用。在病态肥胖症的背景下，仅研究了这些基因/基因座中的少数。我们的主要假设是，遗传变异赋予减肥疗法的抵抗力，并抑制减肥诱导的合并条件分辨率。迄今为止，在饮食和手术体重减轻中仅评估了一些少数候选基因的小研究。该提案的具体目标是首先通过对经历了谨慎的低温减肥计划和Roux-en-Y-Y胃旁路手术的个体中的基因分型来确定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。所有与性状相关的标记将在独立队列中验证。然后，我们将通过直接测序选定的候选基因的直接测序以及与Ansabochip基因座相关的优先基因来鉴定与减肥结果相关的罕见遗传变异。最后，我们将通过在肝脏RNA中分析肝基因表达并确定与这些基因相关的常见变体和稀有变体，其表达水平与体重减轻结果相关。这些目标的完成将增强我们对病态肥胖人群饮食和手术干预后体重减轻结果的分子机制的理解。