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公斤/平方米，与多种代谢紊乱的风险增加有关，包括2型糖尿病(T2D)、高血压(HTN)、包括高甘油三酯血症(HiTRI)和低高密度脂蛋白(LoHDL)在内的血脂异常，以及心血管疾病和总死亡率。病态肥胖(BMI&GT；40公斤/平方米)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。减肥在降低这些风险以及改善疾病严重性方面是有效的，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法可以产生小到中等程度的体重减轻，这可能对合并症有重大影响，但在许多患者中很难实现或维持。因此，减肥手术已经成为病态肥胖患者长期减肥的一种高效疗法，最近又成为一种潜在的治愈2型糖尿病的外科疗法。然而，在特定的共病条件下，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者饮食和手术体重减轻的分子和遗传决定因素，以及与解决共病情况相关的因素。根据遗传力和连锁研究，以及全基因组关联研究，遗传变异似乎在肥胖和相关的共病疾病中起着重要作用。在病态肥胖的背景下，只有几个这些基因/位点被研究过。我们的主要假设是，基因变异使人对减肥疗法产生抵抗力，并抑制减肥诱导的共病症状的解决。到目前为止，只有几个候选基因的小规模研究在饮食和外科减肥方面进行了评估。该提案的具体目标是首先通过对接受了谨慎的低热量减肥计划和Roux-en-Y胃旁路手术的个人的“代谢物芯片”SNPs进行基因分型，确定与减肥结果相关的常见基因变异。然后，我们将测试SNPs与减肥结果之间的关联。所有与性状相关的标记都将在独立的队列中进行验证。然后，我们将通过对选定的候选基因进行直接测序，以及与代谢物芯片基因座相关的优先基因的排序，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中肝脏基因的表达情况，确定其表达水平与减肥结果相关的基因，并确定与这些基因相关的常见和罕见变体。这些目标的完成将增强我们对病态肥胖人群在饮食和手术干预后减肥结果异质性背后的分子机制的理解。 公共卫生相关性：严重肥胖的人患有许多健康问题，如糖尿病、高血压和高胆固醇。减肥可以帮助一些人(但不是所有人)解决这些问题，那些试图通过节食或手术减肥的人往往会恢复体重。对于为什么会发生这种情况，人们知之甚少。这项研究将确定基因是否会影响人们的减肥方式，以及他们的医疗问题是否会得到改善。确定这些因素可能有助于指导在极度肥胖的人群中应该进行哪些类型的减肥治疗。

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.