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Curtailing Smoking Addiction: Ongoing Challenges

Curtailing Smoking Addiction: Ongoing Challenges. Laura Jean Bierut, MD November 15th, 2013. Smoking – A world wide problem. Almost 1 billion people smoke 10 million cigarettes are consumed per minute 5 million deaths per year Over 440,000 deaths in the U.S. per year

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Curtailing Smoking Addiction: Ongoing Challenges

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  1. Curtailing Smoking Addiction:Ongoing Challenges Laura Jean Bierut, MD November 15th, 2013

  2. Smoking – A world wide problem • Almost 1 billion people smoke • 10 million cigarettes are consumed per minute • 5 million deaths per year • Over 440,000 deaths in the U.S. per year • Largest cause of preventable death

  3. Current smoking rates have leveled off (CDC data) • Increased social pressure, policy changes, heightened awareness of health consequences are not enough.

  4. Genetic Variation Drives Smoking Behavior and Nicotine Dependence

  5. Model of Nicotine Dependence - A many step process influenced by genetic and environmental factors Never Use Initiation First puff – First cigarette Smoker 100 cigarettes lifetime Nicotine Dependence

  6. Genetic factors strongly influence the transition to nicotine dependence Never Use Initiation First puff – First cigarette Smoker 100 cigarettes lifetime Nicotine Dependence

  7. Fagerström Test for Nicotine Dependence Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. (1991). The Fagerstrom Test For Nicotine Dependence: A revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction 86:1119-1127.

  8. Thorgeirsson et al., 2010 TAG Consortium, 2010 Liu et al., 2010

  9. Genome Wide Association with Cigarettes per DayA Proxy for Nicotine Dependence Chromosome 15 contains the strongest genetic contribution to the risk of developing nicotine dependence. TAG Consortium., 2010

  10. 15q25: Nicotinic Receptor Gene Cluster Nicotinic Acetylcholine Receptor Improgo, et al., ProgNeurobiol. 2010 Oct;92(2):212-26

  11. SNPrs16969968 • Strongest association with risk of nicotine dependence across multiple studies • Located in CHRNA5 gene • Change from G → A changes AA 398 from asparagine to aspartic acid

  12. Nicotine Metabolism Cytochrome P450 70-80% Nicotine Cotinine H O ~ 10% other metabolites ~ 10% excreted unchanged in urine

  13. CYP2A6 Function and Smoking • Among smokers, reduced CYP2A6 metabolism is associated with: • decreased smoking quantity. • greater success of quitting. Swan & Lessov-Schlaggar, J Neurogenetics. 2009;23:262-271

  14. Smoking Behavior and Genetic Risk Belsky, et al.,. JAMA Psychiatry. 2013;70(5):534-542.

  15. Smoking Behavior and Genetic Risk • Individuals with high genetic risk: • More likely to convert to daily smokers. • Progress more rapidly from initiation to heavy smoking. • Persisted longer with heavy smoking • Develop nicotine dependence more frequently. • More likely to fail cessation attempts. Belsky, et al.,. JAMA Psychiatry. 2013;70(5):534-542.

  16. Nature, 2008 Nature, 2008 Nature Genetics, 2008

  17. Genome Wide Association with Lung Cancer Chromosome 15 contains the strongest genetic contribution to the risk of developing lung cancer. Timofeeva et al., 2012

  18. Nicotinic receptor function and nicotine metabolism are strong lung cancer risks Overall Light smokers Wassenaar, et al., JNCI. 2011;103(17):1342-1346.

  19. CHRNA5 rs16969968 – A delay in smoking cessation Proportion Continuing to Smoke rs16969968 genotype + AA + GA + GG 4 year delay in the first quartile of quitting 2 year delay in the median age of quitting Lung cancer Age of Diagnosis AA – 61 years AG – 64 years GG – 66 years p = 0.001 Spitz et al., 2008 JNCI Age of Quitting Smoking AGE at Cessation Chen et al

  20. Cessation and Remission- The Final Step Initiation Cigarette Use Nicotine Dependence Cessation and Remission

  21. Both CHRNA5 andCYP2A6 inform smoking cessation treatment Counseling alone Counseling + NRT Abstinence Chen, Bloom, et al, 2013

  22. Laura Bierut November 2012 Data from Dr. Thomas Bailey and Josh Doherty

  23. Laura Bierut November 2011 Data from Dr. Thomas Bailey and Josh Doherty

  24. Change is the one constant

  25. Phenotypic and genetic data are available to qualified investigators through the NIDA Genetics Consortium and dbGaP.

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