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Genetic Determinants of Smoking Cessation
Genome-wide Association Studies polymorphisms in the DRD2 receptor associated with decreased protein
Genome-wide association studies (GWAS) allow an unbiased function. One SNP is an insertion/deletion polymorphism (-141C Ins/Del)
assessment of allele frequencies distributed across the entire genome, located in the promoter region of the DRD2 gene.
79
The -141C Ins C allele
rather than alleles in a particular gene. Using this unbiased approach, results in higher transcriptional efficiency of the gene, resulting in more
genes previously overlooked by candidate gene studies may be D2 receptors available to bind dopamine.
79
Lerman and colleagues
identified as risk factors for nicotine dependence or the ability of an demonstrated that smokers homozygous for the Ins C allele had a more
individual to cease smoking. The initial GWAS by Bierut and colleagues
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favourable response to treatment with bupropion than individuals
focused on genetic determinants associated with the Fagerstrom test carrying a Del C allele. However, smokers carrying the Del C allele were
for nicotine dependence (FTND).
69,70
The study identified 35 SNPs across statistically more likely to quit smoking with NRT than homozygous
the genome that marked 14 genes.
68
The results of this study led to a carriers for the Ins C allele.
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The authors concluded from this study that
second-phase candidate gene study that demonstrated that bupropion treatment was most effective in smokers homozygous for the
polymorphisms in the nicotinic receptor gene cluster on chromosome Ins C allele, possibly due to its ability to inhibit dopamine re-uptake,
15, which include 5 nicotinic acetylcholine receptor subunit (CHRNA5), 3 which may replace the hedonic (pleasurable) effects from smoking more
nicotinic acetylcholine receptor subunit (CHRNA3), and β4 nicotinic effectively than NRT in these patients.
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In addition, smokers with the
acetylcholine receptor subunit (CHRNB4), are associated with smoking- combination of the -141 Del allele in the DRD2 gene and variation in the
related behaviours.
71
In addition, a number of novel candidate genes neuronal calcium sensor-1 protein (FREQ), which regulates DRD2
were identified that are involved in biological processes associated with function, were found to respond with greater efficacy to NRT
cell adhesion, cell communication and cell development.
68
However, treatment.
81
Smokers with the variant T allele of a second SNP in the
following correction for multiple analyses these associations did not DRD2 gene (C597T) or Taq1 A1 allele,
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which results in decreased
remain statistically significant. Since these studies, a number of GWAS binding to the dopamine D2 receptor, also have greater rates smoking
approaches of increasing sophistication have identified a number of cessation, but neither NRT nor bupropion enhanced cessation rates in
genes and genome variants that predispose an individual to nicotine these individuals.
80
However, later studies identified that the Taq1 A1
dependence
72–75
or affect nicotine metabolism.
76
Interestingly, these allele was actually present on the ankyrin repeat and kinase domain
studies have also identified genes affecting cell–cell communication and containing 1 gene (ANKK1), and was found to be associated with a
extracellular matrix molecules, which is consistent with the idea that greater efficacy for smoking cessation with a transdermal NRT patch
neuron plasticity is a key determinant in an individual’s dependence on compared with smokers homozygous for the more common A2 allele.
80
nicotine and/or other drug addictions.
72,77
Importantly, the most recent Short-term efficacy of the transdermal patch was also associated with a
GWAS by Drgon et al.
74
also addresses concerns about study recruitment synonymous SNP in the dopamine beta hydroxylase (DBH) gene, which
methods as their findings from a research volunteer population were codes for an enzyme involved in the conversion of dopamine to
found to converge with results from previous GWAS by Bierut et al.,
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Uhl norepinephrine.
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However, subsequent studies have not been able
et al.
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and Liu et al.
75
Drgon and colleagues report on 30 genes to replicate this finding.
59,84–86
associated with nicotine dependence that were identified in the
previous studies by Bierut et al.
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and Liu et al.
75
and five with quit Two functional genetic variations in the dopamine D4 receptor (DRD4)
success genes that overlap with the Uhl et al. study.
73
From these results, associated with decreased protein function have also been investigated.
two genes in particular – ataxin 2-binding protein 1 (A2BP1) and CUB and One is a variable number of tandem repeats (VNTRs) in exon 3 (long
Sushi multiple domains 1 (CSMD1) – were identified in both of the versus short repeat allele), of which the long repeat allele was
analyses,
74
thus supporting the notion that many of the genetic associated with a worse response to placebo and NRT;
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the other is a
associations previously reported in GWAS are not due to recruitment SNP in the promoter region of the gene (C-521T), but no association with
methods and/or the definition used for nicotine addiction, but also smoking cessation was found.
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represent smokers in the general population who seek to quit smoking.
However, like all GWAS these candidates need to be replicated in studies Additional genes associated with the dopaminergic pathway include the
that also account for ethnicity, gender, cohort size and the statistical catabolic dopamine enzyme gene COMT. The common (Val108/158Met)
methods used. Despite these limitations, GWAS have provided several functional polymorphism in the COMT gene results in low activity of the
novel genetic determinants and therefore potential promising enzyme which is involved in the degradation and inactivation of
therapeutic targets for nicotine addition. the neurotransmitter dopamine.
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Female smokers with the low-activity
Met allele are more likely to abstain from smoking with NRT but not
Pharmacogenetic Trials of Treatment for bupropion treatment, but no effect was demonstrated in men.
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Finally,
Nicotine Dependence a nine-repeat variant allele of the dopamine transporter gene
The emerging field of phamacogenetics is based on the premise that SCL6A2 associated with increased transporter availability
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has also
inherited genetic variants contribute to an individual’s response to been associated with greater efficacy of NRT and bupropion therapy.
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treatment in terms of toxicity and efficacy. Although a rapidly developing
field, the stringent experimental control of type and dose of treatment The second focus for nicotine dependence pharmacogenetic trials has
may potentially provide a clearer picture of genetic determinants that been nicotine metabolism. Eighty per cent of nicotine is metabolised by
affect smoking cessation.
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the liver enzyme CYP2A6, and variants of the gene are associated
with slower metabolism.
63
Only one study has demonstrated an
Candidate Gene Pharmacogenetic Trials association with reduced CYP2A6 activity with the efficacy of NRT
The majority of NRT and bupropion pharmacogenetic trials initially (transdermal patch) indirectly by measuring the metabolites of nicotine
focused on genes associated with the dopaminergic pathway due to the trans-3’-hydroxycotine and cotinine.
91
As bupropion is metabolised by
key role of dopamine in substance abuse and the inhibition of dopamine another cytochrome P450 liver enzyme – CYP2B6
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– which is also
reuptake by bupropion. This has lead to the analysis of three functional involved in brain metabolism of nicotine,
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the initial placebo-controlled
EUROPEAN RESPIRATORY DISEASE 39
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