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

4. 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.

5. Genetic Variation Drives Smoking Behavior and Nicotine Dependence

6. 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

7. 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

8. 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:

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

10. 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

11. 15q25: Nicotinic Receptor Gene Cluster
Nicotinic Acetylcholine Receptor
Improgo, et al., Prog Neurobiol Oct;92(2):212-26

12. SNP rs
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

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

14. 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:

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

16. 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):

18. Nature, 2008
Nature, 2008
Nature Genetics, 2008

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

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

21. CHRNA5 rs16969968 – A delay in smoking cessation
Proportion Continuing to Smoke
rs 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

22. 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

23. 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

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

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

26. Change is the one constant

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