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摄入超过能量需求的食物引起的。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，这是影响食物摄入停止的一个因素。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（如TCF7L2）的发展有关。本研究计划旨在进一步研究候选基因与胃功能（胃排空率、胃容量和最大耐受容量作为敏感性标志）之间的关系，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DK67071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，控制肾上腺素能和血清素能功能的三个基因的特异性标记（ADR2A、GNB3和5- HTTLPR）与西布曲明治疗后的体重减轻显著相关。在这项建议中，我们试图扩大这些基因（ADR2A， GNB3和5-HTTLPR）的标记或遗传变异，并探索流行病学研究中与肥胖相关的其他基因（解偶联蛋白[UCP]， FTO和II型DM [TCF7L2]）对饱腹感和饱腹感的外周决定因素的影响，通过经验证的测量胃排空的固体和液体通过显像，胃体积通过SPECT，通过营养饮料测试饱腹感，通过标准化自助餐测试饱腹感。我们的总体长期目标是确定影响周围胃肠功能的易感基因，减少饱腹感和肥胖易感性，并显著改变西布曲明对体重的反应。识别这些基因也将有助于选择那些应该受益于针对胃肠功能的新的肥胖预防或治疗的人。我们的具体目标是：首先，比较具有FTO、ADRB3、解偶联蛋白-2、ADR2A、GNB3等位基因变异位点的超重和肥胖成年人与具有普通等位基因的成年人的最大耐受量、餐后饱腹感、胃排空、禁食和餐后调节量。第二个目的是比较非糖尿病患者、非肥胖和空腹血糖受损的糖尿病相关TCF7L2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。第三个目的是评估在肥胖和超重的成年人中，与具有普通或疾病保护等位基因的成年人相比，具有相同候选基因等位基因变异的肥胖和超重成年人，与安慰剂相比，每天服用西布曲明15毫克，持续12周后体重减轻的药理学调节作用。除了关于西布曲明药物遗传学的具体信息外，本研究还将确定胃功能异常的遗传易感性，未来可能通过药物治疗或改变胃功能、增加用餐饱腹感和诱导停止进食的装置来治疗。因此，该方法有可能预防那些有遗传易感性的肥胖，并选择患者进行外周靶向减肥治疗。

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.