Hackett_q6.qxp 7/8/09 3:59 pm Page 40
Smoking Cessation
trial of bupropion focused on the CYP2B6 gene. The study demonstrated either bupropion or NRT.
73
The study provides initial evidence that
that smokers who were carriers of the CYP2B6 variant, and therefore the genetic determinants underlying successful smoking cessation
were slower metabolisers of nicotine, had higher relapse cessation with NRT are not identical to the genetics underlying successful
rates, which were attenuated with bupropion treatment.
94
However, this smoking cessation with bupropion. In the study, SNPs associated
effect may have been driven by the genotype effect on the placebo with successful smoking cessation with bupropion therapy were
response and not in response to bupropion treatment. In a subsequent shown to be located in the CYP2B7P1/CYP2B6 gene cluster, which is
study of a novel functional CYP2B6*6 variant (a genotype containing two important for generating bupropion’s pharmacologically active
SNPs), smokers with this genotype also had a greater cessation rate with metabolite hydroxybupropion.
73
Interestingly, the SNPs associated
bupropion treatment compared to placebo, whereas smokers with the with treatment success also overlapped with SNPs associated with
wild-type genotype performed equally well on placebo and bupropion.
95
substance-dependence vulnerability genes in the study.
73
Although
Other gene variants associated with smoking cessation therapy replication of these data is required, the study provides additional
outcome include the mu opiate receptor (OPRM1) gene Asp40 variant molecular genetic evidence that smoking cessation has polygenic
(G allele) associated with reduced messenger RNA (mRNA) and protein genetic components that could be used to individualise therapeutic
levels of the mu opiate receptor.
58
The study by Lerman and colleagues approaches for successful smoking cessation therapies.
demonstrated that smokers with the OPRM1 Asp40 variant were more
likely to quit smoking with NRT (transdermal patch) treatment than those Clinical Implications and Future Management
homozygous for the Asn40 variant.
59
Hutchison et al. demonstrated that To date, there are significant data to support the role of genetic
smokers with the TC genotype in the β4 nicotinic acetylcholine receptor variations in response to buproprion and NRT therapy. Importantly,
subunit (CHRNA4) gene, which is associated with greater nicotine many of the genetic variants such as CYP2A6*1 (77%) and DRD2 A1
binding to the α
4
β
2
nAChR and sensitivity to nicotine, were also more (43%) are very common, suggesting that smoking cessation
likely to cease smoking using the nicotine nasal spray, but not the therapies designed using this knowledge would be effective for
transdermal patch.
96
Finally, as some antidepressants are selective the majority of smokers. However, much additional work is needed
serotonin re-uptake inhibitors, variants of the serotonin transporter to validate these findings to provide a more complete
gene 5-HTTLRP have also been investigated. However, no associations understanding of how genetic variability can influence vulnerability
between 5-HTTLRP variants and smoking cessation have been found to nicotine addiction and/or smoking cessation. While genetic
with response to placebo, NRT or bupropion therapy.
97,98
screening in clinical practice is premature at this time, the rapid
development of molecular and statistical methods now applied in
Genome-wide Association Pharmacogenetic Trials phamacogenetic trials for nicotine cessation therapies will
A recent study by Url et al. is the only GWAS to date to identify genes hopefully provide guidance for individualised smoking cessation
associated with smoking cessation success in smokers treated with therapies in the future. ■
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40 EUROPEAN RESPIRATORY DISEASE
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