Pharmacogenomics of Gastric Function & Weight in Obesity

描述(申请人提供)：肥胖是由于食欲增加或食物摄入量超过能量需求而引起的。先前的研究已经确认，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(如脂肪质量和肥胖相关基因，FTO)或II型糖尿病(如TCF7L2)的发生有关。这项研究计划试图进一步检查与胃功能(胃排空率、胃容量和最大耐受量作为敏感性标志)的候选基因的关联，这些候选基因与进食时饱腹感有关。一些候选基因影响肥胖症治疗的效果。在DK67071的前一个周期中，我们的研究团队在一项随机对照临床试验中证明，控制肾上腺素能和5-羟色胺能功能的三个基因(ADR2A、GNB3和5-HTTLPR)的特定标记物与西布曲明的减肥显著相关。在这项建议中，我们寻求扩大这些基因(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])对饱腹感和饱足感的外围决定因素的影响，方法是通过放射性核素对固体和液体的胃排空、SPECT的胃容量、营养饮料试验的饱足感和标准化自助餐的饱足感进行验证。我们的总体和长期目标是识别影响外周胃肠功能、减少饱腹感和易患肥胖症的易感基因，并显著改变对西布曲明的体重反应。识别这些基因还将有助于选择哪些人应该受益于针对胃肠功能的肥胖症的新预防或治疗。我们的具体目标是：首先，比较FTO、ADRB3、解偶联蛋白-2、ADR2A、GNB3等位基因变异的超重和肥胖者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、空腹和餐后调节量。第二个目的是比较携带糖尿病相关TCF7L2等位基因的非糖尿病患者、非肥胖者和空腹血糖受损的成年人与携带糖尿病保护性等位基因的人的相同功能。第三个目标是评估在肥胖和超重成年人中，与服用安慰剂12周相比，每天服用15毫克西布曲明对减肥的药物遗传调节作用，这些成年人的相同候选基因与具有共同或疾病保护等位基因的成年人相比存在等位基因变异。除了关于西布曲明的药物遗传学的具体信息外，这项研究还将确定胃功能异常的遗传易感性，未来可能会使用药物疗法或设备来治疗这些疾病，这些药物或设备可以改变胃功能，增加用餐期间的饱腹感，并导致停止进食。因此，这种方法有可能预防那些具有遗传易感性的人的肥胖，并选择患者进行外周靶向减肥治疗。 与公共健康相关：之前的研究表明，人类胃的功能有助于在进食时感到饱腹感；这种感觉在肥胖者中会减少，可能受到遗传基因的影响。这项研究项目检查哪些候选基因影响肥胖者进食时与饱腹感相关的胃功能，以及哪些基因影响肥胖症药物西布曲明的减肥效果，以便选择合适的患者使用这种药物治疗肥胖症。

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.