Pharmacogenomics of Gastric Function & Weight in Obesity

描述（由申请人提供）：肥胖是由于食欲增加或食物摄入超过能量需求。先前的研究已经确定，人类胃的功能是进食时饱腹感的重要决定因素，这是影响停止进食的一个因素。许多候选基因与肥胖（如脂肪量和肥胖相关基因，FTO）或II型糖尿病（DM，如TCF 7 L2）的发生相关。这项研究计划旨在进一步研究候选基因与胃功能（胃排空率，胃容量和最大耐受量作为敏感性标志）的关联，这些功能与进食时的饱腹感有关。一些候选基因影响肥胖治疗的有效性。在DK 67071的前一个周期中，我们的研究小组在一项随机对照临床试验中证明，控制肾上腺素能和肾上腺素能功能的三个基因（ADR 2A，GNB 3和5- HTTLPR）的特异性标志物与西布曲明引起的体重减轻显著相关。在这个提议中，我们寻求扩大这些基因中的标记或遗传变异（ADR 2A、GNB 3和5-HTTLPR），并在流行病学研究中探索与肥胖相关的其他基因的作用（解偶联蛋白[UCP]、FTO和II型DM [TCF 7 L2]）对饱食和饱腹感的外周决定因素的影响，通过SPECT测定胃容量，通过营养饮料试验测定饱腹感，通过标准化自助餐测定饱腹感。我们的总体长期目标是确定影响外周胃肠道功能、减少饱足感和肥胖易感性以及显著改变西布曲明体重反应的易感基因。识别这些基因也将有助于选择那些应该从针对胃肠道功能的肥胖症新预防或治疗中受益的人。我们的具体目标是：首先，比较在FTO、ADRB 3、解偶联蛋白-2、ADR 2A、GNB 3位点具有等位基因变体的超重和肥胖成人与具有共同等位基因的成人的最大耐受容量、餐后饱足、胃排空、空腹和餐后调节容量。第二个目的是比较非糖尿病患者、非肥胖患者和空腹血糖受损的成年人（糖尿病相关TCF 7 L2等位基因携带者）与糖尿病保护等位基因携带者的相同功能。第三个目的是评估药物遗传学调节的体重减轻响应西布曲明15毫克每天相比安慰剂12周在肥胖和超重的成年人与等位基因变异在相同的候选基因相比，成人常见或疾病保护等位基因。除了关于西布曲明的药物遗传学的具体信息外，这项研究还将确定对胃功能异常的遗传易感性，在未来，可以通过药物治疗或改变胃功能的装置来治疗，增加进食期间的饱腹感并诱导停止进食。因此，该方法有可能预防遗传易感性人群的肥胖，并选择患者进行外周靶向减肥治疗。 公共卫生相关性：先前的研究表明，人类胃的功能有助于在进食时产生饱腹感;这种感觉在肥胖人群中减少，可能受到遗传基因的影响。该研究项目检查了哪些候选基因影响肥胖人群在进食时与饱腹感相关的胃功能，以及哪些基因影响肥胖药物西布曲明的减肥反应，以选择合适的患者用这种药物治疗肥胖。

DESCRIPTION (provided by applicant): Obesity arises from increased appetite or ingestion of food over energy requirement. Previous research has identified that the functions of the human stomach are important determinants of fullness while eating, a factor that influences cessation of food intake. Many candidate genes have been associated with development of either obesity (e.g. fat mass and obesity-associated gene, FTO) or type II diabetes mellitus (DM, e.g. TCF7L2). This research proposal seeks to further examine the association of candidate genes with stomach functions (rate of gastric emptying, gastric volume and maximum tolerated volume as a marker of sensitivity) that are associated with fullness while eating. Some candidate genes influence the effectiveness of obesity treatment. In the prior cycle of DK67071, our research team demonstrated, in a randomized controlled clinical trial, that specific markers of three genes controlling adrenergic and serotonergic function (ADR2A, GNB3 and 5- HTTLPR) are significantly associated with weight loss in response to sibutramine. In this proposal, we seek to expand the markers or genetic variants in these genes (ADR2A, GNB3 and 5-HTTLPR) and to explore effects of other genes that are associated with obesity in epidemiological studies (uncoupling proteins [UCP], and FTO, and type II DM [TCF7L2]) on peripheral determinants of satiation and satiety though validated measurements of gastric emptying of solids and liquids by scintigraphy, gastric volume by SPECT, satiation by nutrient drink test and satiety by standardized buffet meal. Our overall, long term aim is to identify susceptibility genes that influence peripheral gastrointestinal functions, reduce satiation and predispose to obesity and that significantly modify weight response to sibutramine. Identifying those genes will also facilitate selection of people who should benefit from new prevention or treatment for obesity directed at the gastrointestinal functions. Our specific aims are: first, to compare maximum tolerated volume, postprandial satiation, gastric emptying, fasting and postprandial accommodation volume in overweight and obese adults with allelic variants at the FTO, ADRB3, uncoupling protein-2, ADR2A, GNB3 loci to adults with common alleles. A second aim is to compare the same functions in non-diabetics, non-obese and adults with impaired fasting glucose who are carriers of the diabetes-associated TCF7L2 allele vs. those with the diabetes-protective allele. A third aim is to assess the pharmacogenetic modulation of weight loss in response to sibutramine 15 mg per day compared to placebo for 12 weeks in obese and overweight adults with allelic variation in the same candidate genes compared to adults with common or disease-protecting alleles. Apart from the specific information about the pharmacogenetics of sibutramine, this research will identify genetic susceptibility to abnormal stomach function that, in the future, may be treated with pharmacotherapy or devices that change gastric function, increase fullness during meals and induce cessation of feeding. Thus, the approach has potential to prevent obesity in those with genetic susceptibility, and to select patients for peripherally targeted weight loss therapies. PUBLIC HEALTH RELEVANCE: Previous research has shown that the functions of the human stomach contribute to feeling full while eating; this feeling is reduced in obese people and it may be influenced by inherited genes. This research project examines which candidate genes influence stomach functions associated with fullness while eating among obese people, and which genes influence weight loss in response to the obesity medication, sibutramine, in order to select the right patients for treatment of obesity with this medication.