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

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.