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 Largest cause of preventable death

Current smoking rates have leveled off (CDC data) Year % of US adults who were current smokers 2004 21% 2005 2007 20% 2008 2009 2010 19% 2011 CDC MMWR Make table? Lung cancer is the most common cause of cancer death worldwide 2004: 21% (20.9%) of US adults were current cigarette smokers 2005: 21% (20.9%) 2006: 21% (20.8%) 2007: 20% (19.8%) 2008: 21% (20.6%) 2009: 21% (20.6%) 2010: 19% (19.3%) Increased social pressure, policy changes, heightened awareness of health consequences are not enough.

Genetic Variation Drives Smoking Behavior and Nicotine Dependence

First puff – First cigarette Model of Nicotine Dependence - A many step process influenced by genetic and environmental factors Never Use Initiation First puff – First cigarette The process of becoming nicotine dependence is a many step process- It involves the initiation of smoking, in other words, who will take a first puff of a cigarette. Many antismoking campaigns focus on this first step of initiation, encouraging adolescents not to smoke. The next step on the pathway to nicotine dependence is the development of regular smoking. Regular smoking is defined in many studies as smoking 100 cigarettes or more. Most individuals who pass this threshold of smoking 100 or more cigarettes go on to smoke daily. Nicotine dependence represents the step where individuals who are regular smokers develop tolerance and withdrawal. Tolerance develops so that the individual needs to smoke more in order to get the same effect. Withdrawal is where characteristics unpleasant symptoms develop when nicotine no longer used. Smoker 100 cigarettes lifetime Nicotine Dependence 6

First puff – First cigarette Genetic factors strongly influence the transition to nicotine dependence Never Use Initiation First puff – First cigarette The process of becoming nicotine dependence is a many step process- It involves the initiation of smoking, in other words, who will take a first puff of a cigarette. Many antismoking campaigns focus on this first step of initiation, encouraging adolescents not to smoke. The next step on the pathway to nicotine dependence is the development of regular smoking. Regular smoking is defined in many studies as smoking 100 cigarettes or more. Most individuals who pass this threshold of smoking 100 or more cigarettes go on to smoke daily. Nicotine dependence represents the step where individuals who are regular smokers develop tolerance and withdrawal. Tolerance develops so that the individual needs to smoke more in order to get the same effect. Withdrawal is where characteristics unpleasant symptoms develop when nicotine no longer used. Smoker 100 cigarettes lifetime Nicotine Dependence 7

Fagerström Test for Nicotine Dependence Questions Response Options Score How soon after you wake up do you smoke your first cigarette? Within 5 minutes 6-30 minutes 31-60 minutes After 60 minutes 3 2 1 Do you find it difficult to refrain from smoking in places where it is forbidden, e.g., in church, at the library, in cinema, etc.? Yes No Which cigarette would you hate most to give up? The first one in the morning All others How many cigarettes per day do you smoke? 10 or less 11-20 21-30 31 or more Do you smoke more frequently during the first hours after waking than during the rest of the day? Do you smoke if you are so ill that you are in bed most of the day? 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.

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

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

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

SNP rs16969968 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

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

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

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

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.

Nature, 2008 Nature, 2008 Nature Genetics, 2008

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

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

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 Starting at age 20, some people start to quit smoking, most people quit between age 40 and 60. We often look at median age of quitting or first quartile age of quitting to get an idea of the effect size. Individuals with the high risk genotype, AA, have a 2-year delay in median age of quitting compared with those with the low risk genotype, GG. Quitting at 56 vs. 54. If we look at first quartile age of quitting (when 25% of the sample quit), those with AA have a 4-year delay compared with those with GG. Quitting at 41 vs. 45. Age of Quitting Smoking AGE at Cessation Chen et al

Cessation and Remission- The Final Step Initiation Cigarette Use The process of becoming nicotine dependence is a many step process- It involves the initiation of smoking, in other words, who will take a first puff of a cigarette. Many antismoking campaigns focus on this first step of initiation, encouraging adolescents not to smoke. The next step on the pathway to nicotine dependence is the development of regular smoking. Regular smoking is defined in many studies as smoking 100 cigarettes or more. Most individuals who pass this threshold of smoking 100 or more cigarettes go on to smoke daily. Nicotine dependence represents the step where individuals who are regular smokers develop tolerance and withdrawal. Tolerance develops so that the individual needs to smoke more in order to get the same effect. Withdrawal is where characteristics unpleasant symptoms develop when nicotine no longer used. Nicotine Dependence Cessation and Remission 22

Both CHRNA5 and CYP2A6 inform smoking cessation treatment Counseling alone Counseling + NRT Abstinence this NNT is so high because there is essentially no benefit to medication. CHRNA5 Low risk High risk High risk CYP2A6 NNT >1000 16.6 3.7 2.6 Chen, Bloom, et al, 2013

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

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

Change is the one constant

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