Pathways To Precision Medicine In Smoking Cessation Treatments

Abstract

Introduction: Cigarette smoking is highly addictive and prevalent among individuals with mental illness. Modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. MethodsWe investigated the significant genetic variants that predict nicotine dependence, smoking cessation, and response to cessation pharmacotherapy using both large cohort studies of smokers and randomized controlled trials. ResultsWe find that genetic risks may predict prognosis and response to pharmacological treatments. For prognosis, the nicotinic receptor genotypes predict delayed quitting and earlier lung cancer diagnoses after adjusting for smoking quantity in large meta-analyses of studies of lung cancer and nicotine dependence. For treatment response, some pharmacogenetic findings have been replicated in meta-analyses or multiple smoking cessation trials for both pharmacodynamic markers (e.g., CHRNA5) and pharmacokinetic marker (e.g., CYP2A6). The variation in efficacy between smokers with different genetic markers supports the notion that personalized smoking cessation intervention based upon genotype could maximize the efficiency of such treatment while minimizing side effects, thus influencing the number needed to treat (NNT) and the number needed to harm. ConclusionCurrent evidence strongly suggests that cessation failure and cessation pharmacotherapy effectiveness are modulated by biomarkers such as nicotinic receptor genotypes, nicotine metabolism ratio (NMR), or polygenic risk scores for nicotine dependence. These findings strengthen the case for further research on genetics of smoking cessation success, and the development and rigorous testing of treatments for smokers with different genetic risk profiles. Learning Objectives1) human genetic studies can inform the biological mechanisms of nicotine dependence and health consequences such as lung cancer, 2) pharmacogenetic studies may inform personalized treatments for tobacco use disorder, possibly increasing efficacy and reducing risk of side effects.