The objectives of the proposed research are to identify novel genes contributing to nicotine metabolism and smoking cessation and to prospective smoking cessation. Nicotine metabolism is associated with the number of cigarettes smoked per day (CPD), how cigarettes are smoked (smoking topography), responsiveness to smoking cessation treatment, and with carcinogen activation and level. Addiction to nicotine remains the largest modifiable risk factor and contributes to 30% of mortality in the U.S., with 0.5 M individuals dying annually from smoking. We will identify genes associated with nicotine metabolism (pharmacokinetic (PK) genes) through analysis of existing and novel genotype data in samples with fixed dose nicotine metabolic rate (fixed dose NMR) data obtained through a clinical laboratory protocol. We will validate the novel PK genes using random dose NMR data obtained from treatment-seeking smokers, and will investigate whether variation at these novel PK genes influences prospective smoking cessation. These analyses will be the first to explicitly translate PK SNPs associated with the fixed dose NMR from individuals participating in a clinical laboratory protocol to the random dose NMR obtained from treatment-seeking smokers participating in a clinical trial sample, and then into multiple RCTs to investigate association wih prospective smoking cessation (overall and by pharmacotherapy). The number of Cohorts (10) and the number of individuals to be genotyped (3,784) represent the largest collection of informative studies and individuals to be genotyped to identify PK SNPs associated with nicotine metabolism and prospective smoking cessation. Enhanced knowledge of the genetic variation that influences nicotine metabolism and smoking cessation clinical trial outcomes will improve our understanding of metabolism, identify novel targets for the development of smoking cessation therapies, and help characterize PK gene variant effects on smoking behaviors, response to smoking cessation treatment and tobacco-attributable disease.

Public Health Relevance

The objectives of the proposed research are to identify novel genes contributing to nicotine metabolism and to smoking cessation. Nicotine metabolism is associated with the number of cigarettes smoked per day (CPD), how cigarettes are smoked (smoking topography), with responsiveness to smoking cessation treatment, and with carcinogen activation and level. Enhanced knowledge of the genes that influence nicotine metabolism and smoking cessation clinical trial outcomes will identify novel targets for the development of smoking cessation therapies, and may help personalize smoking cessation treatment and genetic risk assessment for smoking- attributable disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA033813-02
Application #
8454451
Study Section
Special Emphasis Panel (ZRG1-PSE-K (03))
Program Officer
Rutter, Joni
Project Start
2012-04-15
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$239,832
Indirect Cost
$98,352
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Schuit, Ewoud; Panagiotou, Orestis A; Munafò, Marcus R et al. (2017) Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers. Cochrane Database Syst Rev 9:CD011823
Baurley, James W; Edlund, Christopher K; Pardamean, Carissa I et al. (2016) Smokescreen: a targeted genotyping array for addiction research. BMC Genomics 17:145
Baurley, James W; Edlund, Christopher K; Pardamean, Carissa I et al. (2016) Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries. Nicotine Tob Res 18:1837-1844
Bergen, Andrew W; Krasnow, Ruth; Javitz, Harold S et al. (2015) Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures. BMC Public Health 15:866
Leung, Tiffany; Bergen, Andrew; Munafò, Marcus Robert et al. (2015) Effect of the rs1051730-rs16969968 variant and smoking cessation treatment: a meta-analysis. Pharmacogenomics 16:713-20
Bergen, Andrew W; Michel, Martha; Nishita, Denise et al. (2015) Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption. PLoS One 10:e0126113
Mamoun, Michael; Bergen, Andrew W; Shieh, Jennifer et al. (2015) Biomarkers of Response to Smoking Cessation Pharmacotherapies: Progress to Date. CNS Drugs 29:359-69
Norden-Krichmar, Trina M; Gizer, Ian R; Phillips, Evelyn et al. (2015) Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort. Twin Res Hum Genet 18:727-37
Leventhal, Adam M; Lee, Wonho; Bergen, Andrew W et al. (2014) Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome. Drug Alcohol Depend 138:109-17
Nievergelt, Caroline M; Wineinger, Nathan E; Libiger, Ondrej et al. (2014) Chip-based direct genotyping of coding variants in genome wide association studies: utility, issues and prospects. Gene 540:104-9

Showing the most recent 10 out of 18 publications