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Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

ABSTRACT: The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

SUBMITTER: Bergen AW

PROVIDER: S-EPMC4488893 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

Bergen Andrew W AW Michel Martha M Nishita Denise D Krasnow Ruth R Javitz Harold S HS Conneely Karen N KN Lessov-Schlaggar Christina N CN Hops Hyman H Zhu Andy Z X AZ Baurley James W JW McClure Jennifer B JB Hall Sharon M SM Baker Timothy B TB Conti David V DV Benowitz Neal L NL Lerman Caryn C Tyndale Rachel F RF Swan Gary E GE

PloS one 20150701 7

The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the associ ...[more]

PMID: 26132489

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Project description:ImportanceSmoking cigarettes during pregnancy can impair maternal and child health, and pregnant individuals have increasingly used electronic cigarettes (e-cigarettes) for various reasons, including quitting smoking.ObjectiveTo assess smoking abstinence rates among pregnant individuals who used e-cigarettes compared with those who used nicotine replacement therapy (NRT).Design, setting, and participantsThis cohort study is a secondary data analysis of phase 8 of the US Pregnancy Risk Assessment Monitoring System, conducted between 2016 and 2020. Eligible participants included pregnant individuals who smoked combustible cigarettes within the 3 months before pregnancy and either used e-cigarettes or NRT during pregnancy. Data analysis was conducted from March 2022 to April 2023.ExposuresCombustible cigarette use within 3 months before pregnancy and use of either e-cigarettes or NRT during pregnancy.Main outcomes and measuresThe primary outcome was the individual's self-reported smoking abstinence status during the last 3 months of pregnancy. Weighted percentages were reported and weighted multivariable logistic regression models were used to examine the association of e-cigarette use vs NRT with smoking abstinence. A propensity score was used to control for confounding by sociodemographics, pregnancy characteristics, prepregnancy smoking intensity, depression, behavioral support, and hookah use.ResultsThe cohort included 1329 pregnant individuals (759 ≥25 years [60.2%]; 766 non-Hispanic White individuals [79.8%]) of whom 781 had an education level of high school or lower (61.4%), and 952 had an annual household income of $48 000 or less (81.5%). Of the 1329 individuals, 890 (unweighted percentage, 67.0%) were existing e-cigarette users, 67 (unweighted percentage, 5.0%) were new e-cigarette users, and 372 (unweighted percentage, 28.0%) were NRT users. Compared with individuals who used NRT during pregnancy, individuals who used e-cigarettes had a higher rate of smoking abstinence in late pregnancy (456 individuals [50.8%] vs 67 individuals [19.4%]; propensity score adjusted odds ratio [OR], 2.47; 95% CI, 1.17-5.20; P = .02). In the secondary analysis stratified by the timing of e-cigarette use initiation, existing users of e-cigarettes who initiated before pregnancy had a higher smoking abstinence rate than NRT users (446 users [53.1%] vs 67 users [19.4%]; adjusted OR, 2.61; 95% CI, 1.23-5.51; P = .01). However, new e-cigarette users who initiated use during pregnancy had a similar smoking abstinence rate in late pregnancy when compared with NRT users (10 users [20.6%] vs 67 users [19.4%]; adjusted OR, 1.13; 95% CI, 0.22-5.87; P = .88).Conclusions and relevanceThese findings suggest that individuals who used e-cigarettes during pregnancy had a higher smoking abstinence rate in late pregnancy than individuals who used NRT, especially for those who initiated e-cigarette use before pregnancy, indicating that replacement of cigarettes with e-cigarettes during pregnancy may be a viable strategy for harm reduction.

Project description:Background and aimsSmokers can regulate their nicotine intake by altering the number of cigarettes smoked per day (CPD) and their smoking intensity. The current study aimed to compare the utility of self-reported CPD, total nicotine equivalents (TNE) and urinary cotinine to estimate nicotine intake during pregnancy.DesignLongitudinal smoking behavior and biomarker data were collected at early pregnancy, late pregnancy and at postpartum as part of a smoking cessation trial to examine voucher-based incentives for decreasing smoking.SettingObstetric practices in Burlington, Vermont, United States.ParticipantsA subset of participants (n = 47) from the parent trial, recruited between December 2006 and June 2012, who provided a urine sample at each assessment during early pregnancy, late pregnancy and postpartum.MeasurementsSmoking was assessed using self-reported CPD, TNE, TNE/CPD and urinary cotinine.FindingsPregnant smokers reported smoking 10.4 CPD at early pregnancy, 7.2 CPD at late pregnancy (a 31% reduction at late pregnancy, P = 0.001) and 8.6 CPD at postpartum (a 19% increase from late pregnancy, P = 0.08). TNE exposure was 41% (P = 0.07) and 48% (P = 0.03) lower at early and late pregnancy, respectively, compared to postpartum. TNE/CPD was on average 167% higher at late pregnancy compared to early pregnancy (P = 0.01) and remained high at postpartum, where it was 111% higher compared to early pregnancy (P = 0.007). Uriniary cotinine underestimated nicotine intake by 55% during early pregnancy and by 65% during late pregnancy compared to postpartum (Pinteraction < 0.001); the underestimation was greater in slower (Pinteraction < 0.001) versus faster (Pinteraction = 0.04) nicotine metabolizers.ConclusionsNeither cigarettes smoked per day (CPD) nor cotinine provides an accurate estimate of nicotine exposure during pregnancy. CPD underestimates nicotine intake substantially due to under-reporting and/or higher intensity of smoking, while cotinine underestimates nicotine intake markedly due to accelerated nicotine (and cotinine) metabolism during pregnancy.

Dataset Information

Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

Publications

Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

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