Full length articleInterplay of genetic risk (CHRNA5) and environmental risk (partner smoking) on cigarette smoking reduction
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
References (45)
- et al.
Why do women continue to smoke in pregnancy?
Women Birth
(2007) - et al.
Spousal influence on smoking behaviors in a US community sample of newly married couples
Soc. Sci. Med.
(2005) Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution
Biol. Psychiatry
(2014)- et al.
New methods for tobacco dependence treatment research
Ann. Behav. Med.
(2011) - et al.
Time to first cigarette in the morning as an index of ability to quit smoking: implications for nicotine dependence
Nicotine Tob. Res.
(2007) - et al.
Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes
Nicotine Tob. Res.
(2009) - et al.
Nicotinic acetylcholine receptor variation and response to smoking cessation therapies
Pharmacogenet. Genomics
(2013) - et al.
Nicotine dependence and the a5-a3-b4 nicotinic receptor gene cluster: variants in the nicotinic receptors alter the risk for nicotine dependence
Am. J. Psychiatry
(2008) - et al.
The Wisconsin Predicting Patients’ Relapse questionnaire
Nicotine Tob. Res.
(2009) - et al.
Biomarkers for smoking cessation
Clin. Pharmacol. Ther.
(2013)
Prospective association of dopamine-related polymorphisms with smoking cessation in general care
Pharmacogenomics
Predicting smoking cessation and major depression in nicotine-dependent smokers
Am. J. Public Health
Dissection of the phenotypic and genotypic associations with nicotinic dependence
Nicotine Tob. Res.
Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success
Am. J. Psychiatry
The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes
Nicotine Tob. Res.
Nicotinic acetylcholine receptor beta2 subunit gene implicated in a systems-based candidate gene study of smoking cessation
Hum. Mol. Genet.
Use of genetic markers and gene–diet interactions for interrogating population-level causal influences of diet on health
Genes Nutr.
Estimates of nondisclosure of cigarette smoking among pregnant and nonpregnant women of reproductive age in the United States
Am. J. Epidemiol.
Cohort profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort
Int. J. Epidemiol.
A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy
Hum. Mol. Genet.
ALSPAC—the Avon Longitudinal Study of Parents and Children. I. Study methodology
Paediatr. Perinat. Epidemiol.
Factors associated with smoking relapse in the postpartum period: an analysis of the child health surveillance system data in Southeast England
Nicotine Tob. Res.
Cited by (16)
Genomic medicine to reduce tobacco and related disorders: Translation to precision prevention and treatment
2023, Addiction NeuroscienceA systematic review of genetic variation within nicotinic acetylcholine receptor genes and cigarette smoking cessation
2022, Drug and Alcohol DependenceCitation Excerpt :Studies were excluded if they did not have a smoking cessation outcome or used a genetic risk score as the independent variable. Also excluded were news stories, commentaries, letters to the editor, review papers, heritability (e.g., family or twin studies) or linkage studies, studies with ≤ 1-month follow-up, studies that used the same data and tested the same SNPs as another study (Conti et al., 2008; Chen et al., 2014a). We also excluded studies from the meta-analysis that reported findings for SNPs that were not reported in another citation in relation to associations with smoking cessation outcomes (i.e. “novel SNPs”).
The role of nicotinic receptor genes (CHRN) in the pathways of prenatal tobacco exposure on smoking behavior among young adult light smokers
2018, Addictive BehaviorsCitation Excerpt :Additionally, rs2304297 tags a variant in CHRNB3A6 that is protective against smoking heaviness in adult smokers (Cannon, Mermelstein, Hedeker, et al., 2014; Pugach, Cannon, Weiss, Hedeker, & Mermelstein, 2017). The risk conveyed by CHRNA5A3B4 HA also extends to PTE specifically: HA is associated with heavier and continued smoking during pregnancy (Chen, Baker, Piper, et al., 2014; Freathy, Ring, Shields, et al., 2009). Thus, it is possible that PTE impacts smoking heaviness in offspring via inheritance of HA rather than via an intrauterine effect.
Pathways to precision medicine in smoking cessation treatments
2018, Neuroscience LettersCitation Excerpt :As a result, some studies show an association between CHRNA5 and smoking cessation [63–67], whereas other studies do not [69–71]. It is likely that the expression of this genetic risk on cessation varies with several factors, such as developing a smoking-related disease such as COPD or lung cancer [27], the use of cessation pharmacotherapy [28], or environmental influences on smoking cessation, such as living with a partner who smokes [90]. The effect of this genetic locus is seen most clearly in subjects whose environment strongly influences them to quit smoking, have no smoking-related disorder, and have not used cessation medicine.
CHRNA5-A3-B4 and DRD2 Genes and Smoking Cessation Throughout Adulthood: A Longitudinal Study of Women
2023, Nicotine and Tobacco Research