Genetic Determinants of Weight Loss and Resolution of Co-Morbidities

描述（由申请人提供）：肥胖，通常定义为身体质量指数（BMI）大于30 kg/m2，与许多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，因此减轻病态肥胖患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等程度的体重减轻，这可能对合并症产生重大影响，但在许多患者中难以实现或维持。因此，减肥手术已成为病态肥胖患者长期减肥的一种非常有效的治疗方法，最近又被用作治疗2型糖尿病的一种手术治疗方法。然而，在特定的合并症中体重减轻和改善的程度是可变的。我们的长期目标是确定病态肥胖患者饮食和手术减重的分子和遗传决定因素，以及与合并症解决相关的因素。基于遗传力和连锁研究，以及全基因组关联研究，遗传变异似乎在肥胖和相关合并症中起着重要作用。在病态肥胖的背景下，只有少数这些基因/基因座被研究过。我们的主要假设是，遗传变异赋予了对减肥疗法的抗性，并抑制了减肥引起的合并症的解决。迄今为止，只有少数候选基因的小型研究在饮食和手术减肥中得到了评估。本提案的具体目标是首先通过对经过谨慎低热量减肥计划和Roux-en-Y胃旁路手术的个体进行“代谢芯片”snp基因分型，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系。所有性状相关标记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代谢芯片位点相关的优先基因的直接测序，确定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。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异质性的分子机制的理解。

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.