Freathy RM, Ring SM, Shields B, Galobardes B, Knight B, Weedon MN et al.. 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 18: 2922-2927

Genetics of Complex Traits, Peninsula Medical School, Institute of Biomedical and Clinical Science, Magdalen Road, Exeter EX1 2LU, UK.
Human Molecular Genetics (Impact Factor: 6.39). 06/2009; 18(15):2922-7. DOI: 10.1093/hmg/ddp216
Source: PubMed

ABSTRACT Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes. Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some pregnant women continue to smoke. A recent genome-wide association study demonstrated an association between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy, we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds (95% CI 1.11-1.45) of continued smoking during pregnancy (P = 0.0006). Adjustment for pre-pregnancy smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03-1.39); P = 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the first, but not the last, trimester [OR for smoking 10+ cigarettes/day versus 1-9/day in first trimester = 1.30 (95% CI 1.13-1.50); P = 0.0003]. To conclude, we have found strong evidence of association between the rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the previously observed association with smoking quantity. Our data support the role of genetic factors in influencing smoking cessation during pregnancy.

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Available from: Andrew Hattersley, Feb 20, 2015
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    • "Finally in our comparison of offspring of mothers, who quit smoking before pregnancy, and mothers, who continued to smoke, we assumed that these groups were comparable with respect to environmental and genetic background variables. This may not be the case, however, as the ability to quit, even among established smokers may be related to genetic influences (Freathy et al. 2009). "
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    ABSTRACT: Maternal smoking during pregnancy (SDP) is associated with increased risk of externalizing and internalizing behaviors in offspring. Two explanations (not mutually exclusive) for this association are direct causal effects of maternal SDP and the effects of genetic and environmental factors common to parents and offspring which increase smoking as well as problem behaviors. Here, we examined the associations between parental SDP and mother rated offspring externalizing and internalizing behaviors (rated by the Child Behavior Checklist/2-3) at age three in a population-based sample of Dutch twins (N = 15,228 pairs). First, as a greater effect of maternal than of paternal SDP is consistent with a causal effect of maternal SDP, we compared the effects of maternal and paternal SDP. Second, as a beneficial effect of quitting smoking before pregnancy is consistent with the causal effect, we compared the effects of SDP in mothers who quit smoking before pregnancy, and mothers who continued to smoke during pregnancy. All mothers were established smokers before their pregnancy. The results indicated a greater effect of maternal SDP, compared to paternal SDP, for externalizing, aggression, overactive and withdrawn behavior. Quitting smoking was associated with less externalizing, overactive behavior, aggression, and oppositional behavior, but had no effect on internalizing, anxious depression, or withdrawn behavior. We conclude that these results are consistent with a causal, but small, effect of smoking on externalizing problems at age 3. The results do not support a causal effect of maternal SDP on internalizing behaviors.
    Behavior Genetics 09/2015; DOI:10.1007/s10519-015-9738-2 · 3.21 Impact Factor
    • "Further studies have demonstrated change in the receptor function in response to nicotine agonists given this amino acid change in the ␣5 nicotinic receptor subunit (Bierut et al., 2008; Brown et al., 2007). Growing evidence indicates that rs16969968 in CHRNA5 is a predictor for smoking cessation in some circumstances and predicts a delay in successful smoking cessation (Baker et al., 2009; Bergen et al., 2013; Chen et al., 2012, 2015; Freathy et al., 2009; Munafo et al., 2011; Sarginson et al., 2011; Zhu et al., 2014). Using data from the University of Wisconsin Transdisciplinary Tobacco Use Research Center (UW-TTURC), we have previously shown that CHRNA5 gene modulates clinical response to NRT. "
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    ABSTRACT: Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X(2)=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 06/2015; 154. DOI:10.1016/j.drugalcdep.2015.06.022 · 3.42 Impact Factor
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    • "For example , Mendelian randomization leverages genetic associations with environmental exposures while protecting against reverse causality and (under certain assumptions) confounding (Ebrahim and Davey Smith, 2008). The identification of variants associated with smoking cessation, including during pregnancy, provides an opportunity to implement this technique (Freathy et al., 2009; Munafò et al., 2011), and this approach has been successfully applied to establish the effects of continuing to smoke during pregnancy on offspring birth weight (Tyrrell et al., 2012). However, the magnitude of the effects of common genetic variants on complex behaviour outcomes such as smoking during pregnancy means that single genetic variants are weak instruments. "
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    ABSTRACT: Background Comparison of the associations of maternal and mother's partner smoking with offspring outcomes is, in theory, a useful method for assessing whether there may be an intrauterine effect of tobacco exposure on these outcomes. However, this approach assumes that the effects of passive smoking from exposure to partner smoking during pregnancy are minimal. We evaluated this assumption using a biochemical measure of tobacco exposure in pregnant women. Methods Cotinine levels taken during the first trimester of pregnancy were measured in a sample of 3,928 women from the Avon Longitudinal Study of Parents and Children. Median cotinine values were compared across categories of smoking heaviness (cigarettes per day) of the women during the first trimester and in non-smoking women by the smoking heaviness of their partner. Results Cotinine levels were substantially higher in women who smoked compared to non-smokers (range of medians across smoking heaviness categories: 900 to 5,362 ng/ml versus 20 ng/ml, interquartile range (IQR) (0 to 63) for non-smokers). In contrast, cotinine levels in non-smoking women were only very weakly related to partner smoking status (range of medians in women with smoking partners: 34 to 69 ng/ml versus 12 ng/ml, IQR (0 to 48) in women with non-smoking partners). Conclusions Levels of tobacco exposure from partner smoking, as assessed by cotinine, were low in non-smoking pregnant women. This suggests that using mother's partner's smoking as a negative control for investigating intrauterine effects is valid.
    Drug and alcohol dependence 06/2014; 139(100). DOI:10.1016/j.drugalcdep.2014.03.012 · 3.42 Impact Factor
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