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Genomics and personalized medicine: CHRNA5-CHRNA3-CHRNB4 and smoking cessation treatment.

ABSTRACT: Cigarette smoking is highly addictive, and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We review the significance of variants in the nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) in the prediction of smoking quantity, smoking cessation, and response to cessation medication in multiple studies of smoking cessation. Three common haplotypes (low-risk, intermediate-risk, and high-risk) in the CHRNA5-CHRNA3-CHRNB4 region are defined by rs16969968 and rs680244. The genetic variants in the CHRNA5-CHRNA3-CHRNB4 region that predict nicotine dependence also predict a later age of smoking cessation in a community-based sample. In a smoking cessation trial, these variants predict abstinence at end of treatment in individuals receiving placebo medication, but not amongst individuals receiving active medication. Pharmacological treatments moderate the genetic risk in affecting cessation success. These pharmacogenetic interactions have been reproduced by a recent meta-analysis of smoking cessation trials. The number needed to treat (NNT) is 4 for smokers with the high-risk haplotype, 7 for smokers with the intermediate-risk haplotype, and >1000 for smokers with the low-risk haplotype. The wide variation in NNT between smokers with different haplotypes supports the notion that personalized smoking cessation intervention based upon genotype could meaningfully increase the efficiency of such treatment. In summary, variants in the CHRNA5-CHRNA3-CHRNB4 region identify individuals at increased risk of cessation failure, and this increased risk can be ameliorated by cessation pharmacotherapy.

SUBMITTER: Chen LS

PROVIDER: S-EPMC4158847 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Genomics and personalized medicine: <i>CHRNA5-CHRNA3-CHRNB4</i> and smoking cessation treatment.

Chen Li-Shiun LS Bierut Laura J LJ

Journal of food and drug analysis 20131201 4

Cigarette smoking is highly addictive, and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We review the significance of variants in the nicotinic receptor gene cluster (<i>CHRNA5-CHRNA3-CHRNB4</i>) in the prediction of smoking quantity, smoking cessation, and response to cessation ...[more]

PMID: 25214750

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Project description:IntroductionReducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step toward this goal. In 2012, King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5-CHRNA3-CHRNB4 region on gastrointestinal adverse events and to extend the analyses to adherence and smoking cessation.MethodsThe University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression.ResultsGastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation.ConclusionsVariants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication.ImplicationsThe fact that our findings from the TTURC smoking cessation trial support the independent findings of King et al. suggest that associations of variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.

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Genomics and personalized medicine: CHRNA5-CHRNA3-CHRNB4 and smoking cessation treatment.

Publications

Genomics and personalized medicine: <i>CHRNA5-CHRNA3-CHRNB4</i> and smoking cessation treatment.

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