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.

项目概要/摘要 肥胖治疗的基石——饮食、体力活动和行为改变——未能产生足够的 大多数人的长期减肥临床指南建议添加抗肥胖药物。 (AOM) 当保守方法不是最佳时，即使使用 AOM，也存在很大的范围。 个体间体重减轻的差异表明存在“反应者”和“无反应者”。 对 AOM 的反应强调了肥胖的异质性以及更加个性化治疗的需要 鉴于肥胖具有很强的遗传性，可能是由于病因因素存在个体差异。 遗传因素在个体对特定药物治疗的反应中发挥作用。该提案的重点是。 FDA 批准的 AOM Contrave 是纳曲酮和安非他酮 (NB) 两种药物的组合。 纳曲酮是一种 µ-阿片受体 (MOPR) 拮抗剂，安非他酮可抑制多巴胺和 去甲肾上腺素的临床试验表明，治疗 56 周后体重平均减轻 6.1%； 然而，只有 48% 的患者体重达到临床显着减轻 5%。 NB 可能的作用机制使得解决反应变异性背后的原因成为可能。 安非他酮成分可激活阿片黑皮质素原 (POMC) 神经元，这是减少食物摄入量的关键调节因子 摄入并刺激能量消耗，部分通过刺激多巴胺 D2 受体发生 (DRD2)。我们推测纳曲酮还可以通过结合 MOPR 来激活 POMC 神经元。 对 NB 的反应可能是由于位于锚蛋白重复序列​​和激酶中的 Taq1A 遗传变异 (rs1800497) 含有结构域的蛋白 1 (ANKK1) 基因，与 DRD2 基因相邻 携带至少一个次要基因的个体。 rs1800497 多态性的等位基因（称为 Taq1A A1+）代表了大约 45% 的人群，并且有 30- 这些人的大脑 DRD2 可能相对缺乏 POMC 的多巴胺能激活。 因此，我们预测它们将从弥补这种缺陷的药物中获得最大的益处。 考虑到假设，我们进行了一项概念验证试点研究，审查了接受 NB 治疗的患者的图表， 确实发现，与非 Taq1A A1+ 基因型携带者相比，Taq1A A1+ 基因型携带者的体重减轻反应更大 携带者，表明该基因型可用于预测成功的减肥。 严格检验 Taq1A A1+ 多态性的存在与体重增加相关的假设 与A1-基因型相比，NB的体重减轻在停止药物治疗后维持体重减轻。 在目标二中，我们还将探索可能影响疗效的其他基因多态性。 NB 并确定血清催乳素水平（中枢多巴胺能张力的测量）是否可以用作全身性指标 帮助预测药物反应的生物标志物最终目标是将药物遗传学纳入肥胖研究。 药物以最大限度地提高效果并限制不必要的成本和药物副作用的暴露 给个别患者带来的好处微乎其微。