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Curtailing Smoking Addiction:Ongoing Challenges

Laura Jean Bierut, MDNovember 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

19001906

19121918

19241930

19361942

19481954

19601966

19721978

19841990

19962002

20080

500

1000

1500

2000

2500

3000

3500

4000

4500

5000US Cigarette Consumption 1900 - 2010

Year

Per C

apita

Cig

arett

e Co

nsum

ption

per capita cigarette consumption

Death rates sources: Public-use data files, National Vital Statistics System, National Center for Health Statistics, Centers for Disease Control and Prevention; and Jemal et al., CA Cancer J Clin, 2010. Cigarette consumption sources: Tobacco Outlook Report, Economic Research Service, US Department of Agricul-ture; and Alcohol and Tobacco Trade and Tax Bureau, US Department of Treasury.

Current smoking rates have leveled off (CDC data)

• Increased social pressure, policy changes, heightened awareness of health consequences are not enough.

Year% of US adults who

were current smokers2004 21%2005 21%2004 21%2007 20%2008 21%2009 21%2010 19%2011 19%

Genetic Variation Drives Smoking Behavior and Nicotine Dependence

Model of Nicotine Dependence - A many step process influenced by genetic and environmental

factors

InitiationFirst puff – First cigarette

Smoker100 cigarettes lifetime

Nicotine Dependence

Never Use

Genetic factors strongly influence the transition to nicotine dependence

InitiationFirst puff – First cigarette

Smoker100 cigarettes lifetime

Nicotine Dependence

Never Use

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.

Questions Response Options Score

1. How soon after you wake up do you smoke your first cigarette?

Within 5 minutes6-30 minutes

31-60 minutesAfter 60 minutes

3210

2. 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.?

YesNo

10

3. Which cigarette would you hate most to give up? The first one in the morningAll others

10

4. How many cigarettes per day do you smoke? 10 or less11-2021-30

31 or more

0123

5. Do you smoke more frequently during the first hours after waking than during the rest of the day?

YesNo

10

6. Do you smoke if you are so ill that you are in bed most of the day?

YesNo

10

Thorgeirsson et al., 2010

TAG Consortium, 2010

Liu et al., 2010

Genome Wide Association with Cigarettes per DayA Proxy for Nicotine Dependence

TAG Consortium., 2010

Chromosome 15 contains the strongest genetic contribution to the risk of developing nicotine dependence.

15q25: Nicotinic Receptor Gene Cluster

Improgo, et al., Prog Neurobiol. 2010 Oct;92(2):212-26

Nicotinic Acetylcholine Receptor

SNP rs16969968

• Located in CHRNA5 gene• Change from G → A changes AA 398

from asparagine to aspartic acid

• Strongest association with risk of nicotine dependence across multiple studies

HO

Nicotine Metabolism

NicotineCytochrome P450

70-80%

Cotinine

~ 10% excreted unchanged in urine

~ 10% other metabolites

CYP2A6 Function and Smoking

Swan & Lessov-Schlaggar, J Neurogenetics. 2009;23:262-271

• Among smokers, reduced CYP2A6 metabolism is associated with: decreased smoking quantity. greater success of quitting.

Smoking Behavior and Genetic Risk

Belsky, et al.,. JAMA Psychiatry. 2013;70(5):534-542.

Smoking Behavior and Genetic Risk

Belsky, et al.,. JAMA Psychiatry. 2013;70(5):534-542.

Individuals with high genetic risk:

1. More likely to convert to daily smokers.

2. Progress more rapidly from initiation to heavy smoking.

3. Persisted longer with heavy smoking

4. Develop nicotine dependence more frequently.

5. More likely to fail cessation attempts.

19001906

19121918

19241930

19361942

19481954

19601966

19721978

19841990

19962002

20080

500

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2000

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5000

0

10

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70US Cigarette Consumptions and Lung Cancer Deaths,

1900 - 2010

Year

Per C

apita

Cig

arett

e Co

nsum

ption

Lung Cancer Death Rate*(age-adjusted, per 100,000)

per capita cigarette consumption

Death rates sources: Public-use data files, National Vital Statistics System, National Center for Health Statistics, Centers for Disease Control and Prevention; and Jemal et al., CA Cancer J Clin, 2010. Cigarette consumption sources: Tobacco Outlook Report, Economic Research Service, US Department of Agricul-ture; and Alcohol and Tobacco Trade and Tax Bureau, US Department of Treasury.

Lung cancerdeath rate

Nature Genetics, 2008

Nature, 2008

Nature, 2008

Genome Wide Association with Lung Cancer

Timofeeva et al., 2012

Chromosome 15 contains the strongest genetic contribution to the risk of developing lung cancer.

Nicotinic receptor function and nicotine metabolism are strong lung cancer risks

Wassenaar, et al., JNCI. 2011;103(17):1342-1346.

Overall

Light smokers

21

CHRNA5 rs16969968 – A delay in smoking cessation

Age of Quitting Smoking

Prop

ortio

n C

ontin

uing

to S

mok

e

rs16969968 genotype+ AA+ GA+ GG

AGE at Cessation

4 year delay in the firstquartile of quitting

2 year delay in the medianage of quitting

Chen et al

Lung cancer Age of DiagnosisAA – 61 yearsAG – 64 yearsGG – 66 yearsp = 0.001

Spitz et al., 2008 JNCI

Cessation and Remission- The Final Step

Initiation

Cigarette Use

Nicotine Dependence

Cessation and Remission

Abstinence

Both CHRNA5 and CYP2A6 inform smoking cessation treatment

CHRNA5 Low risk High risk Low risk High riskCYP2A6 Low risk Low risk High risk High risk

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

placebo

NRT

Counseling alone

Counseling + NRT

NNT >1000 16.6 3.7 2.6Chen, Bloom, et al, 2013

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

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 investigatorsthrough the NIDA Genetics Consortium and dbGaP.