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

项目摘要/摘要 肥胖治疗的基石--饮食、体力活动和行为矫正--不能产生足够的 大多数人的长期减肥效果。临床指南建议增加抗肥胖药物 (AOM)当保守方法不是最优的时候。然而，即使使用AOM，也有很大的范围 个体间的体重减轻表明有“响应者”和“非响应者”。中的可变性 对AOMS的反应突显了肥胖症的异质性，以及对更个性化治疗的需求 解释了病因上的个体差异。考虑到肥胖的强大遗传性，有可能 遗传因素在个体对特定药物治疗的反应中发挥作用。这项提案的重点是 FDA批准的AOM，Contrave，这是两种药物的组合，纳曲酮和安非他酮(NB)。 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的再摄取和 去甲肾上腺素。NB的临床试验显示，治疗56周后，体重平均下降6.1%； 然而，只有48%的患者在临床上实现了体重显著减少5%。了解以下内容 NB可能的作用机制使解决可能导致反应差异的因素成为可能。 安非他酮成分激活前阿片黑素皮质素(POMC)神经元，这是减少食物摄入量的关键调节因素 摄取和刺激能量消耗，部分通过刺激多巴胺D2受体发生 (DRD2)。纳曲酮还通过结合MOPR激活POMC神经元。我们推测，一些可变性 对NB的反应可能是由于Taq1A基因突变(Rs1800497)位于Ankyrin Repeat和Kinase 含结构域蛋白1(ANKK1)基因，与DRD2基因相邻。携带至少一名未成年人的个人 Rs1800497多态的等位基因(称为Taq1AA1+)约占人群的45%，具有30- 大脑DRD2减少40%。这些个体可能在POMC的多巴胺能激活方面存在相对缺陷 因此，我们预测神经元将从一种弥补这种缺陷的药物中获得最大的好处。有了这个 在考虑假设的情况下，我们进行了一项概念验证先导性研究，回顾了使用NB和 确实发现，携带Taq1AA1+基因的携带者比不携带Taq1AA1+基因的携带者有更大的减肥反应 携带者的研究表明，该基因可用于预测成功的减肥效果。在目标一中，我们建议 严格检验Taq1AA1+多态与体重增加相关的假设 与A1-型相比，Nb基因缺失。停止药物治疗后保持体重减轻 也将接受评估。在第二个目标中，我们将探索其他可能影响疗效的基因多态。 并确定血清催乳素水平，一种衡量中枢多巴胺能张力的指标，是否可用于全身 帮助预测药物反应的生物标记物。最终的目标是将药物遗传学与肥胖结合起来。 药物，以最大限度地发挥效果，限制不必要的成本和药物副作用的暴露 对个别患者的益处微乎其微。

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.