Smoking is a significant public health problem, and there is a great need for research to improve smoking cessation treatment outcomes. The goal of the Pharmacogenetics of Nicotine Addiction Treatment (PNAT) research program is to generate the evidence base to optimize treatment decisions for Individuals who want to quit smoking. During the past 4 years of PNAT1, we have characterized genetic variants altering nicotine pharmacokinetics as well as pharmacodynamic genetic variants influencing response to pharmacotherapies for smoking cessation treatment. We have shown that the CYP2A6 enzyme is critical in the metabolic inactivation of nicotine, and inherited variation in nicotine clearance influences smoking behavior and cessation. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR;3'hydroxycotinine/cotinine), which reflects both genetic and environmental influences on CYP2A6 activity and nicotine clearance. The NMR is measured noninvasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of therapeutic response in multiple independent (retrospective) clinical trials. Translation of these findings to clinical practice, the ultimate goal of the PGRN, requires validation In a prospective stratified clinical trial comparing alternative therapies for smoking cessation. In this competing renewal, we propose to conduct a prospective placebo-controlled multi-center pharmacogenetic (PGx) clinical trial of alternative therapies for smoking cessation treatment in 1,350 smokers. Randomization to placebo, transdermal nicotine, or varenicline will be stratified prospectively based on the NMR, the most robust genetically-informed biomarker for smoking cessation identified to date. Further, to facilitate translation to practice, we will determine the cost-effectiveness of our proposed PGx approach using both primary data and simulation models. In addition to these goals, we propose within this UOI to: identify additional sources of genetic variation in nicotine clearance and the NMR;investigate additional pharmacokinetic and pharmacodynamic gene associations with therapeutic response biomarker;and elucidate the mechanisms involved in identified PGx effects on smoking cessation. The proposed research provides the next critical step to validate a genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to optimize treatment decisions for their patients who wish to quit smoking. As outlined recently by NIDA, due to the devastating health consequences of smoking and the urgent demand for better treatments, the validation of biomarker strategies to improve the outcomes of treatments a major public health priority.

Public Health Relevance

The ultimate goal of this research is to validate a genetically-informed diagnostic tool which clinicians can use in the future to optimize treatment decisions for their patients who smoke. Due to the enormous adverse impact of tobacco use, this research has high public health significance.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-M (52))
Program Officer
Walton, Kevin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Li, Sufang; Yang, Yihong; Hoffmann, Ewa et al. (2016) CYP2A6 Genetic Variation Alters Striatal-Cingulate Circuits, Network Hubs, and Executive Processing in Smokers. Biol Psychiatry :
Schwantes-An, Tae-Hwi; Zhang, Juan; Chen, Li-Shiun et al. (2016) Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts. Behav Genet 46:151-69
Benowitz, Neal L; St Helen, Gideon; Dempsey, Delia A et al. (2016) Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity. Pharmacogenet Genomics 26:340-50
Ross, Kathryn C; Gubner, Noah R; Tyndale, Rachel F et al. (2016) Racial differences in the relationship between rate of nicotine metabolism and nicotine intake from cigarette smoking. Pharmacol Biochem Behav 148:1-7
Chenoweth, Meghan J; Schnoll, Robert A; Novalen, Maria et al. (2016) The Nicotine Metabolite Ratio is Associated With Early Smoking Abstinence Even After Controlling for Factors That Influence the Nicotine Metabolite Ratio. Nicotine Tob Res 18:491-5
Ware, Jennifer J; Chen, Xiangning; Vink, Jacqueline et al. (2016) Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2. Sci Rep 6:20092
Rabin, Rachel A; Ashare, Rebecca L; Schnoll, Robert A et al. (2016) Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial. Am J Addict 25:291-6
Hatsukami, Dorothy K; Severson, Herbert; Anderson, Amanda et al. (2016) Randomised clinical trial of snus versus medicinal nicotine among smokers interested in product switching. Tob Control 25:267-74
Rhodes, Jessica D; Hawk Jr, Larry W (2016) Smoke and mirrors: The overnight abstinence paradigm as an index of disrupted cognitive function. Psychopharmacology (Berl) 233:1395-404
Lerman, Caryn; Schnoll, Robert A; Hawk Jr, Larry W et al. (2015) Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med 3:131-8

Showing the most recent 10 out of 145 publications