Psychobiological /Genetic Determinants-Smoking Cessation

Summary

Principal Investigator: S P David
Abstract: [unreadable] DESCRIPTION (provided by applicant): [unreadable] My career goal is to develop the experience, skills, and infrastructure to become an independent investigator in smoking cessation research with a focus on molecular genetics. This K08 Mentored Clinical Scientist Award proposal outlines a comprehensive, five-year program of supervised research in pharmacogenetic smoking cessation clinical trials with Sponsors Raymond Niaura, Ph.D. at Brown University, and Co-Sponsor Peter Shields, M.D. at Georgetown University, a structured didactic seminar series integrated with the Transdisciplinary Tobacco Use Research Center at Brown University combined with laboratory training in genotyping techniques at Georgetown University and establishment of an independent laboratory at Brown University. This work will be informed by an outstanding network of transdisciplinary mentors and collaborative research with Co-Sponsors at the University of Oxford. The focus of the proposed research is an evaluation of the role of the dopamine transporter SLC6A3 polymorphism, and other dopaminergic candidate gene polymorphisms, in treatment response of smokers to bupropion hydrochloride for smoking cessation. The proposed research would be the first study to explore how genotype and treatment interact through multiple cognitive, behavioral, affective, and physiological endophenotypes to reduce the reinforcing properties of smoking and impact smoking outcomes. [unreadable] [unreadable] The specific aims are: [unreadable] [unreadable] (1) To evaluate the role of the dopamine transporter SLC6A3 polymorphism in treatment response to bupropion for smoking cessation, [unreadable] [unreadable] (2) To test the hypotheses that bupropion diminishes the reinforcing properties of smoking and that the effect of bupropion on reduction of the reinforcing properties of smoking will be significantly greater among smokers who carry DRD2-Taq1 A2/A2 genotypes than it is among smokers with DRD2-Taq1 A1/A1 or A1/A2 genotypes, [unreadable] [unreadable] (3) To investigate the interaction between genotype and cue reactivity among smokers with DRD2-Taq1 A2/A2 and DRD2-Taq1 A1/A1 or A1/A2 genotypes, and [unreadable] [unreadable] (4) To evaluate the impact of additional dopaminergic candidate gene polymorphisms on treatment response to bupropion for smoking cessation and multiple endophenotypes. [unreadable] [unreadable] [unreadable] [unreadable]
Funding Period: 2002-09-27 - 2008-05-31
more information: NIH RePORT

Top Publications

  1. pmc Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion
    Sean P David
    Stanford University School of Medicine, Center for Education and Research in Family and Community Medicine, Division of General Medical Disciplines, Department of Medicine, Stanford, CA, USA SRI International, Center for Health Sciences, Menlo Park, CA, USA Alpert Medical School of Brown University, Department of Family Medicine, Pawtucket, RI, USA
    Addiction 108:2202-11. 2013
  2. pmc Relationship between amounts of daily cigarette consumption and abdominal obesity moderated by CYP2A6 genotypes in Chinese male current smokers
    Tao Liu
    Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat Sen University, Guangzhou, China
    Ann Behav Med 43:253-61. 2012
  3. pmc Associations of CYP2A6 genotype with smoking behaviors in southern China
    Tao Liu
    Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat Sen University, Guangzhou, China
    Addiction 106:985-94. 2011
  4. pmc Dopamine D4 receptor gene variation moderates the efficacy of bupropion for smoking cessation
    A M Leventhal
    Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
    Pharmacogenomics J 12:86-92. 2012
  5. pmc Association of the DRD2 gene Taq1A polymorphism and smoking behavior: a meta-analysis and new data
    Marcus R Munafo
    Department of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK
    Nicotine Tob Res 11:64-76. 2009
  6. pmc Molecular genetics of successful smoking cessation: convergent genome-wide association study results
    George R Uhl
    Molecular Neurobiology Research Branch, National Institutes of Health Intramural Research Program, National Institute on Drug Abuse, 333 Cassell Dr, Ste 3510, Baltimore, MD 21224, USA
    Arch Gen Psychiatry 65:683-93. 2008
  7. ncbi Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: new data from the Patch in Practice trial and pooled analyses
    Sean P David
    Department of Family Medicine, Center for Primary Care and Prevention, The Warren Alpert Medical School of Brown University, 111 Brewster Street, Pawtucket, RI 02806, USA
    Drug Alcohol Depend 98:77-85. 2008
  8. pmc Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects
    George R Uhl
    Molecular Neurobiology Branch, National Institutes of Health NIH, Intramural Research Program IRP, National Institute on Drug Abuse NIDA, Baltimore, MD 21224, USA
    Ann N Y Acad Sci 1141:318-81. 2008
  9. pmc A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation
    Nicky J Welton
    Primary Care, Department, Community Based Medicine, University of Bristol, Bristol, UK
    Nicotine Tob Res 10:231-40. 2008
  10. pmc Chronic cigarette smoking and the microstructural integrity of white matter in healthy adults: a diffusion tensor imaging study
    Robert H Paul
    Department of Psychology, Behavioral Neuroscience, University of Missouri, St Louis, MO 63121, USA
    Nicotine Tob Res 10:137-47. 2008

Scientific Experts

Detail Information

Publications20

  1. pmc Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion
    Sean P David
    Stanford University School of Medicine, Center for Education and Research in Family and Community Medicine, Division of General Medical Disciplines, Department of Medicine, Stanford, CA, USA SRI International, Center for Health Sciences, Menlo Park, CA, USA Alpert Medical School of Brown University, Department of Family Medicine, Pawtucket, RI, USA
    Addiction 108:2202-11. 2013
    ....
  2. pmc Relationship between amounts of daily cigarette consumption and abdominal obesity moderated by CYP2A6 genotypes in Chinese male current smokers
    Tao Liu
    Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat Sen University, Guangzhou, China
    Ann Behav Med 43:253-61. 2012
    ..Cigarette smoking is an important risk factor for abdominal obesity. However, the degree to which the CYP2A6 genotype moderates the relationship between smoking and abdominal obesity has not been established...
  3. pmc Associations of CYP2A6 genotype with smoking behaviors in southern China
    Tao Liu
    Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat Sen University, Guangzhou, China
    Addiction 106:985-94. 2011
    ..To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers...
  4. pmc Dopamine D4 receptor gene variation moderates the efficacy of bupropion for smoking cessation
    A M Leventhal
    Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
    Pharmacogenomics J 12:86-92. 2012
    ..01) and in analyses predicting continuous abstinence (P's≤0.054). Bupropion may be more efficacious for smokers who carry the long allele, which is relevant to personalized pharmacogenetic treatment approaches...
  5. pmc Association of the DRD2 gene Taq1A polymorphism and smoking behavior: a meta-analysis and new data
    Marcus R Munafo
    Department of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK
    Nicotine Tob Res 11:64-76. 2009
    ..There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence...
  6. pmc Molecular genetics of successful smoking cessation: convergent genome-wide association study results
    George R Uhl
    Molecular Neurobiology Research Branch, National Institutes of Health Intramural Research Program, National Institute on Drug Abuse, 333 Cassell Dr, Ste 3510, Baltimore, MD 21224, USA
    Arch Gen Psychiatry 65:683-93. 2008
    ..Smoking remains a major public health problem. Twin studies indicate that the ability to quit smoking is substantially heritable, with genetics that overlap modestly with the genetics of vulnerability to dependence on addictive substances...
  7. ncbi Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: new data from the Patch in Practice trial and pooled analyses
    Sean P David
    Department of Family Medicine, Center for Primary Care and Prevention, The Warren Alpert Medical School of Brown University, 111 Brewster Street, Pawtucket, RI 02806, USA
    Drug Alcohol Depend 98:77-85. 2008
    ..However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers...
  8. pmc Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects
    George R Uhl
    Molecular Neurobiology Branch, National Institutes of Health NIH, Intramural Research Program IRP, National Institute on Drug Abuse NIDA, Baltimore, MD 21224, USA
    Ann N Y Acad Sci 1141:318-81. 2008
    ..Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes...
  9. pmc A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation
    Nicky J Welton
    Primary Care, Department, Community Based Medicine, University of Bristol, Bristol, UK
    Nicotine Tob Res 10:231-40. 2008
    ..In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest...
  10. pmc Chronic cigarette smoking and the microstructural integrity of white matter in healthy adults: a diffusion tensor imaging study
    Robert H Paul
    Department of Psychology, Behavioral Neuroscience, University of Missouri, St Louis, MO 63121, USA
    Nicotine Tob Res 10:137-47. 2008
    ..Additional studies are needed to further explore differences in white matter integrity between smokers and nonsmokers...
  11. ncbi Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study
    Sean P David
    Cancer Research United Kingdom General Practice Research Group, Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, UK
    Biol Psychiatry 58:488-94. 2005
    ..Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity...
  12. pmc Building a successful research enterprise in family medicine: the Brown experience
    Sean P David
    Brown Medical School, USA
    Med Health R I 89:281-4. 2006
  13. pmc The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: follow-up of a randomized controlled trial
    Sean P David
    Center for Primary Care and Prevention, Brown Medical School Memorial Hospital of Rhode Island, Pawtucket, RI 02960, USA
    Nicotine Tob Res 9:225-31. 2007
    ....
  14. pmc Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch
    S P David
    Brown Medical School Memorial Hospital of Rhode Island, Pawtucket, RI, USA
    Pharmacogenomics J 8:122-8. 2008
    ....
  15. pmc Association of COMT Val108/158Met genotype with smoking cessation in a nicotine replacement therapy randomized trial
    Elaine C Johnstone
    Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom
    Cancer Epidemiol Biomarkers Prev 16:1065-9. 2007
    ....
  16. pmc Successful Latino community partnership program for smoking cessation
    Sean P David
    Am J Public Health 97:1348-9; author reply 1349. 2007
  17. pmc Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation
    Sean P David
    Brown University Center for Primary Care and Prevention, Providence, RI 02860, USA
    Nicotine Tob Res 9:821-33. 2007
    ....
  18. pmc Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials
    Sean P David
    Brown University Center for Primary Care and Prevention, Primary Care Genetics and Translational Research Center, Memorial Hospital of Rhode Island, Pawtucket, RI 02860, USA
    Nicotine Tob Res 9:1251-7. 2007
    ..These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype...
  19. pmc A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans
    Sean P David
    Department of Clinical Pharmacology, Cancer Research United Kingdom General Practice Research Group, University of Oxford, Oxford OX2 6HE, United Kingdom
    J Neurosci 25:2586-90. 2005
    ..The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states...