Elsevier

Drug and Alcohol Dependence

Volume 143, 1 October 2014, Pages 36-43
Drug and Alcohol Dependence

Full length article
Interplay of genetic risk (CHRNA5) and environmental risk (partner smoking) on cigarette smoking reduction

https://doi.org/10.1016/j.drugalcdep.2014.06.027Get rights and content

Abstract

Background

This study tests whether the genetic predictor (CHRNA5 nicotine receptor gene variants) and an environmental risk factor (partner smoking) interact in the prediction of smoking reduction.

Methods

Subjects were from a community-based, longitudinal study of women (n = 1856) who smoked before pregnancy, and a randomized comparative effectiveness smoking cessation trial (n = 1065). Smoking reduction was defined as the trajectory of self-reported smoking quantities over time in the observational study, and as the trajectory of alveolar CO levels in the cessation trial.

Results

In the pregnancy study, rs16969968 genotype and partner smoking status interacted such that the smoking reduction was lowest for expectant mothers with high genetic risk and partner smoking, and highest for those with high genetic risk but not partner smoking (interaction of genotype × partner smoking on smoking quantity trajectory slope β = 0.071, 95%CI = 0.013, 0.13, p = 0.017). In the clinical trial, a similar interaction was found (interaction β = 0.20, 95%CI = 0.049, 0.36, p = 0.010). Furthermore, these associations were moderated by pharmacotherapy such that the interactive relation of genetic and environmental factors occurred in the placebo group, but not in the active pharmacotherapy group (interaction of genotype × partner smoking × pharmacotherapy on CO trajectory slope β = −0.25, 95%CI = −0.42, −0.091, p = 0.0023).

Conclusions

The CHRNA5 genetic risk synergized the effect of partner smoking, producing an especially low likelihood of successful smoking reduction in two complementary studies. This suggests that the genetic vulnerability may be mitigated by altering environmental factors. In addition, cessation pharmacotherapy neutralizes the increase in cessation failure associated with combined genetic and environmental risks, which has possible relevance to treatment algorithms.

Introduction

Tobacco smoking is a continuing global public health concern despite effective smoking cessation treatments and public health policies (Jha et al., 2013, Schroeder, 2013, Thun et al., 2013), and rates of smoking cessation failure remain high in both clinical and general populations (Baker et al., 2007, Breslau and Johnson, 2000, West, 2005). Identification of the genetic and environmental predictors of quitting success is critical in understanding the causes of smoking cessation outcomes and developing more effective clinical interventions and health policies.

Growing evidence suggests that genetic variants predict cessation success (Baker et al., 2009, Breitling et al., 2010, Conti et al., 2008, Freathy et al., 2009, King et al., 2012, Munafo et al., 2011, Rose et al., 2010, Sarginson et al., 2011, Uhl, 2009, Uhl et al., 2008, Uhl et al., 2012). Specifically, rs16969968, a non-synonymous coding variant in the nicotinic receptor gene (CHRNA5), is not only unequivocally associated with heavy smoking in multiple large scale meta-analyses, but also is associated with a functionally significant change in nicotinic receptor binding to agonist (Bierut et al., 2008, Liu et al., 2010, Saccone et al., 2010, TAG, 2010, Thorgeirsson et al., 2010, Ware et al., 2011). This CHRNA5 variant has been shown to predict smoking cessation success and response to cessation pharmacotherapy in multiple studies. Individuals with the rs16969968 risk variant (A) are less likely to be abstinent at the end of treatment and more likely to benefit from cessation pharmacotherapy such as nicotine replacement (Bergen et al., 2013, Chen et al., 2012b, Munafo et al., 2011).

Having a partner who smokes is a well-established risk factor for low motivation to quit smoking and failure to quit smoking successfully (Bolt et al., 2009, Harmer and Memon, 2013, Homish and Leonard, 2005, Okechukwu et al., 2012, Ruge et al., 2008). This may be because partner smoking allows immediate access to cigarettes and greater exposure to smoking cues. It is currently unknown how this major environmental risk affects smoking cessation in the context of the major genetic risk (i.e., CHRNA5 risk alleles). It is possible that the two factors merely produce additive effects, or they interact such that one amplifies the risk posed by the other. For instance, it is possible that partner smoking affects only those low in genetic risk; i.e., those high in genetic risk will likely relapse regardless of cigarette availability and exposure. Conversely, it is possible that environmental risk is most damaging to those high in genetic risk; i.e., partner smoking is especially challenging to those with a strong genetic vulnerability to cessation failure. The current research aims to address a clinically significant question: i.e., Do major genetic and environmental risks synergize to produce individuals with an especially high risk of cessation failure?

Using data from a community-based study, the Avon Longitudinal Study of Parents and Children (ALSPAC (Golding et al., 2001)), and a University of Wisconsin Transdisciplinary Tobacco Use Research Center (UW-TTURC; Piper et al., 2009) smoking cessation clinical trial, we examine the main and interactive effects of partner smoking and CHRNA5 genetic risk on smoking reduction likelihood. The two studies differ in type of participants, study duration, and design. However, complementary hypotheses are developed for these two research designs.

The ALSPAC study includes pregnant women smokers who are likely to limit their smoking or quit completely during pregnancy with health and social concerns (Cnattingius, 2004, Triche et al., 2008). In the ALSPAC study, the primary outcome is smoking reduction defined by a trajectory of decreasing self-reported smoking quantity during pregnancy. In the Wisconsin smoking cessation trial, a biomarker for smoking heaviness (alveolar CO level) was assessed both before and after the quit date through 8 weeks post-quit. CO level over time constitutes an objective biomarker of smoking reduction. In sum, smoking reduction is assessed by trajectories of self-reported smoking quantity in a community sample and alveolar CO level in a treatment trial. Use of continuous measures of smoking outcomes provides a more sensitive index of outcome than does a binary measure such as point prevalence abstinence (Baker et al., 2011).

Analyses address these questions: (1) Whether the CHRNA5 effect on smoking reduction is moderated by partner smoking in the observational community study; (2) whether the CHRNA5 effect on smoking reduction is moderated by partner smoking in the cessation trial; and (3) given evidence that the CHRNA5 risk for smoking cessation failure occurs primarily amongst individuals not using pharmacotherapy, does the gene × environmental risk interaction occur only amongst individuals receiving placebo? Given evidence that CHRNA5 risk for smoking cessation varies with pharmacotherapy (Bergen et al., 2013, Chen et al., 2012b), we will also test whether the gene × environmental risk interaction varies with pharmacotherapy.

Section snippets

Avon Longitudinal Study of Parents and Children (ALSPAC)

The ALSPAC study (Fraser et al., 2012, Golding et al., 2001) is a prospective study that recruited pregnant women from Avon, UK, with expected delivery dates between April 1991 and December 1992 (known as Phase I enrollment). The study website contains details of all the data that are available through a fully searchable data dictionary (http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/). All women gave informed consent and ethical approval was obtained from the ALSPAC Law

Avon Longitudinal Study of Parents and Children (ALSPAC)

Subjects were of European descent, identified as smokers pre-pregnancy (defined as active smoking ≥1 cigarettes per day (CPD)), and had genotype data (n = 1856). Demographic data, pre-pregnancy smoking quantity, genotype frequencies are given in Table S1(A)1 and 62.0% of women reported living with a partner who smoked cigarettes. We found a robust association between CHRNA5

Discussion

Our study represents an initial evaluation of the complex interplay of gene, environment, and pharmacotherapy in smoking behaviors. We found, as in prior studies, that the risk variant rs16969968 in CHRNA5 decreases the likelihood of smoking cessation success, as does living with a partner who smokes (Bergen et al., 2013, Bolt et al., 2009, Chen et al., 2012b, Harmer and Memon, 2013, Homish and Leonard, 2005, Munafo et al., 2011, Okechukwu et al., 2012, Ruge et al., 2008). However, across two

Role of funding source

This research was supported by NIH grants P01 CA089392 (LJB), P50 CA84724 (TBB), and K05 CA139871 (TBB) from the National Cancer Institute, P50 DA19706 (TBB), K02 DA021237 (LJB), and K08 DA030398 (LSC) from the National Institute on Drug Abuse, U01 HG004422 (LJB) from the National Human Genome Research Institute, and sub-award KL2 RR024994 (LSC) from the National Center for Research Resources. Genotyping services for the UW-TTURC sample were provided by the Center for Inherited Disease Research

Contributors

Authors Li-Shiun Chen, Timothy Baker, George Davey Smith, Marcus Munafo, and Laura Bierut designed the study. Authors Li-Shiun Chen, Timothy Baker, Marcus Munafo, and Laura Bierut wrote summaries of previous related work. Authors Charles Gu, Megan Piper, Steven Smith, and Rick Grucza advised on the analysis designs and plans. Authors Li-Shiun Chen undertook the statistical analysis, and author Li-Shiun Chen, Timothy Baker, Marcus Munafo, and Laura Bierut wrote the first draft of the manuscript.

Conflict of interest statement

Laura J. Bierut is listed as an inventor on issued U.S. Patent 8,080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. All other authors declare no potential conflict of interest.

Acknowledgments

The Wisconsin State Laboratory of Hygiene provided considerable technical assistance in this research effort. Glaxo Wellcome provided bupropion at no cost in the UW-TTURC clinical trial.

The authors thank John Budde and Nick McKenna for their technical assistance with Open Array platform genotyping, Joseph Mullaney for his assistance in preparing the data, and Sherri Fisher for her assistance in project coordination and editing/preparing the manuscript.

We are extremely grateful to all the

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