Association of genetic variation near the dopamine D2 receptor gene and other polymorphisms that modulate dopaminergic and opioid signaling on the weight loss response to naltrexone/bupropion

多巴胺 D2 受体基因附近的遗传变异与调节多巴胺能和阿片类信号传导对纳曲酮/安非他酮减肥反应的其他多态性的关联

• 批准号: 10586181
• 负责人: Judith Korner
• 金额: $ 59.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586181
• 关键词: Address; Adult; Affect; Alleles; Ankyrin Repeat; Behavior Therapy; Binding; Biological Markers; Body Weight; Body Weight decreased; Body mass index; Brain; Bupropion; Clinical; Clinical Trials; Combined Modality Therapy; Counseling; DRD2 gene; Desire for food; Diet; Diet therapy; Dopamine; Dopamine D2 Receptor; Eating; Energy Metabolism; Enrollment; Esthesia; Etiology; Exposure to; FDA approved; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Guidelines; Heritability; Heterogeneity; Individual; Individual Differences; Knowledge; Learning; Measures; Medicine; Metabolism; Methods; Minor; Naltrexone; Neurons; Norepinephrine; Obesity; Opioid; Opioid Receptor; Other Genetics; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phase; Phosphotransferases; Physical activity; Pilot Projects; Population; Pro-Opiomelanocortin; Prolactin; Proteins; Questionnaires; Recommendation; Rewards; Serum; Signal Transduction; Testing; Time; Weight; antagonist; behavioral phenotyping; clinically significant; comorbidity; cost; density; drug response prediction; fat mass and obesity-associated protein; genetic variant; improved; individual patient; individual response; obesity treatment; personalized medicine; prevent; primary endpoint; prospective; responders and non-responders; response; reuptake; risk variant; side effect; weight maintenance

PROJECT SUMMARY/ABSTRACT The cornerstone of obesity therapy - diet, physical activity and behavioral modification - fails to produce sufficient long-term weight loss in most individuals. Clinical guidelines recommend the addition of anti-obesity medication (AOM) when conservative methods are less than optimal. Yet even with the use of AOM, there is a wide range of inter-individual weight loss suggesting that there are “responders” and “non-responders.” The variability in response to AOMs underscores the heterogeneity of obesity and the need for more personalized treatment that accounts for individual differences in etiologic factors. Given the strong heritability of obesity, it is possible that genetic factors play a role in an individual’s response to a given pharmacotherapy. This proposal focuses on the FDA-approved AOM, Contrave, which is a combination of two medications, naltrexone and bupropion (NB). Naltrexone is a µ-opioid receptor (MOPR) antagonist and bupropion inhibits the reuptake of dopamine and norepinephrine. Clinical trials of NB demonstrate a mean weight loss of 6.1% after 56 weeks of treatment; however, only 48% of patients achieved a clinically significant reduction in body weight of ³5%. Knowledge of the likely mechanisms of action of NB makes it possible to address what might underlie the variability in response. The bupropion component activates the proopiomelanocortin (POMC) neuron, a key regulator in decreasing food intake and stimulating energy expenditure, and occurs in part through stimulation of dopamine D2 receptors (DRD2). Naltrexone also activates POMC neurons by binding MOPR. We postulated that some of the variability in response to NB may be due to the Taq1A genetic variant (rs1800497) located in the ankyrin repeat and kinase domain-containing protein 1 (ANKK1) gene, adjacent to the DRD2 gene. Individuals carrying at least one minor allele of the rs1800497 polymorphism (termed Taq1A A1+) represent about 45% of the population and have 30- 40% fewer brain DRD2. Such individuals likely have a relative deficiency in dopaminergic activation of POMC neurons, thus, we predict they would receive the greatest benefit from a drug that remedies this deficit. With this hypothesis in mind, we conducted a proof-of-concept pilot study reviewing charts of patients treated with NB and indeed found that carriers of the Taq1A A1+ genotype had a greater weight loss response compared with non- carriers, suggesting that this genotype could be used to predict successful weight loss. In Aim One, we propose to rigorously test the hypothesis that presence of the Taq1A A1+ polymorphism is associated with greater weight loss with NB compared with the A1- genotype. Maintenance of weight loss after discontinuation of drug treatment will also be evaluated. In Aim Two, we will explore other genetic polymorphisms that might influence the efficacy of NB and determine if serum prolactin level, a measure of central dopaminergic tone, may be used as a systemic biomarker to help predict drug response. The ultimate goal is to incorporate pharmacogenetics into obesity medicine in order to maximize results and limit unnecessary cost and exposure to side effects of medications that provide minimal benefit to the individual patient.

项目摘要/摘要 肥胖疗法的基石 - 饮食，体育锻炼和行为改变 - 无法产生足够的足够 大多数人的长期体重减轻。临床指南建议添加抗肥胖药物 （AOM）当保守方法不足时。然而，即使使用AOM，也有广泛的范围 个体间的体重减轻，表明有“反应者”和“无反应者”。变异性 对AOM的反应强调了肥胖的异质性以及对更个性化的治疗的需求 说明病因学因素的个体差异。鉴于肥胖的强大遗传力，有可能 遗传因素在个人对给定药物疗法的反应中起作用。该提议重点 FDA批准的AOM，Contrave是两种药物的组合，Naltrexone和Bupropion（NB）。 纳曲酮是µ-阿片受体（MOPR）拮抗剂，安非他酮抑制了多巴胺的再摄取和 去甲肾上腺素。 NB的临床试验表明，治疗56周后，平均体重减轻为6.1％。 但是，只有48％的患者的体重在临床上显着降低了秒秒秒秒秒。知识 NB的作用机制可能使能够解决响应中的可变性的基础。 安非他酮成分激活proopiomelanocortin（POMC）神经元，这是降低食物的关键调节剂 摄入和刺激能量消耗，并部分通过刺激多巴胺D2受体而发生 （DRD2）。纳曲酮还通过结合MOPR激活POMC神经元。我们假设一些可变性 响应于NB，可能是由于位于Ankyrin重复酶和激酶中的TAQ1A遗传变体（RS1800497）引起的 含域的蛋白1（ANKK1）基因，与DRD2基因相邻。携带至少一个未成年人 RS1800497多态性（称为TAQ1A A1+）的等位基因约占人口的45％，具有30- 大脑DRD2少40％。这样的个体可能在POMC的多巴胺能激活中相对缺乏 因此，我们预测神经元将从补救这种辩护的药物中获得最大的好处。与此 考虑到假设，我们进行了概念证明的试点研究，审查了接受NB治疗的患者的图表 确实发现TAQ1A A1+基因型的载体与非 - 载体表明该基因型可用于预测成功的体重减轻。在目标中，我们提出 严格测试TAQ1A A1+多态性的存在与重量更大有关的假设 与A1基因型相比，NB的损失。停用药物治疗后的体重减轻 也将评估。在目标二，我们将探索可能影响效率的其他遗传多态性 NB并确定血清催乳激素水平是否可以用作全身性多巴胺能的度量 生物标志物可帮助预测药物反应。最终目标是将药物遗传学纳入肥胖症 药物以最大化结果并限制不必要的成本和暴露于药物的副作用 这为个别患者提供了最小的好处。