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Smoking Cessation
Genetic Determinants of Smoking Cessation
Tillie-Louise Hackett
Post-doctoral Fellow, James Hogg’s iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia
Abstract
Recent estimates suggest that worldwide more than 5 million people die each year from smoking, which equates to one death every
six seconds. The health benefits of smoking cessation are well documented, but despite the treatments available for tobacco
dependence there remain a considerable number of smokers who have difficulty achieving sustained abstinence from smoking. In
addition to the number of environmental factors (e.g. parental and peer influence, economic status, depression) that can affect the
ability of an individual to cease smoking, epidemiological studies of smoking cessation indicate that genetics plays an important role.
Nicotine dependence is inheritable in ways that substantially overlap with vulnerability to dependence on other addictive substances.
It has also been demonstrated that the heritable influences on successful smoking cessation differ from those that influence aspects
of nicotine dependence. Therefore, understanding the mechanisms that influence an individual to achieve and sustain abstinence from
smoking is essential. The emerging field of phamacogenetics is based on the premise that inherited genetic variants contribute to an
individual’s response to treatment in terms of toxicity and efficacy. This article highlights the most recent candidate gene and
genome-wide association single-nucleotide polymorphism studies that have identified genetic variations that affect the response of a
smoker to buproprion and nicotine replacement therapy. Importantly, many of the genetic variants identified – such as CYP2A6*1 (77%)
and DRD2 A1 (43%) – are very common, suggesting that smoking cessation therapies designed using this knowledge would be effective
for the majority of smokers. However, much additional work is needed to validate these findings to provide a more complete
understanding of how genetic variability can influence vulnerability to nicotine addiction and/or smoking cessation. While genetic
screening in clinical practice is premature at this time, the rapid development of molecular and statistical methods now applied in
phamacogenetic trials for nicotine cessation therapies will hopefully provide guidance for individualised smoking cessation therapies
in the future.
Keywords
Smoking cessation, genetic epidemiology, pharmacogenetic trials
Disclosure: The author has no conflicts of interest to declare.
Received: 13 January 2009 Accepted: 10 June 2009
Correspondence: Tillie-Louise Hackett, Room 166, James Hogg's iCAPTURE Centre for Cardiovascular and Pulmonary Research, St Paul's Hospital, 1081 Burrard Street,
thackett@mrl.ubc.ca
The Tobacco Epidemic Nicotine binds to nicotinic acetylcholine receptors located in the brain,
Tobacco has been identified as the second major cause of death in autonomic ganglia and neuromuscular junctions, leading to the release
the world. Recent estimates suggest that more than 5 million people of a number of neurotransmitters and hormones such as dopamine,
die each year from smoking worldwide, which equates to one death serotonin, norepinephrine, acetylcholine, vasopressin and beta-
every six seconds.
1
Smoking-related illnesses kill around half of all endorphin. It is the release of these mediators that modulates the
smokers,
2–4
which exceeds any other addiction, exposure or injury. In behavioural and cognitive responses such as pleasure, mood and
developing countries, 12.2% of all-cause mortality can be attributed to motor performance.
9
Sustained smoking leads to the development of
cigarette smoking.
5
Despite these devastating health consequences, if ‘tolerance’ to nicotine, which decreases the effect of any given dose of
current smoking patterns continue, tobacco use is still predicted to the drug. Tolerance results from the morphological changes in receptor
cause 8 million deaths each year by 2030.
1,3
To reverse this trend, it is function such as receptor desensitisation and inactivation, as well as
important that efforts are made to improve smoking cessation rates upregulation of receptor number.
10
As a result of these neuro-
as well as to discourage individuals from taking up the habit adaptions, nicotine cessation leads to withdrawal syndrome
(particularly in developing countries). characterised by depression, anxiety, insomnia, decreased heart rate,
irritability and weight gain.
11
Therefore, smokers require periodic and
Smoking Dependence repetitive doses of nicotine, leading to tobacco dependence. For the
Of the 4,500 separate compounds in the gaseous and particulate phase vast majority of smokers, tobacco dependence occurs for the majority
of cigarette smoke,
6,7
nicotine is the main psychoactive component that of their life and several periods of remission and relapse occur before
leads to the dependence-forming properties of tobacco smoking.
8
definitive smoking cessation is achieved.
12,13
© TOUCH BRIEFINGS 2009 37
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