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Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer.

ABSTRACT: The Northern Plains (NP) and Southwest (SW) American Indian populations differ in their smoking patterns and lung cancer incidence. We aimed to compare CYP2A6 genetic variation and CYP2A6 enzyme activity (representative of the rate of nicotine metabolism) between the two tribal populations as these have previously been associated with differences in smoking, quitting, and lung cancer risk.American Indians (N=636) were recruited from two different tribal populations (NP in South Dakota, SW in Arizona) as part of a study carried out as part of the Collaborative to Improve Native Cancer Outcomes P50 Project. A questionnaire assessed smoking-related traits and demographics. Participants were genotyped for CYP2A6 genetic variants *1B, *2, *4, *7, *9, *12, *17, and *35. Plasma and/or saliva samples were used to measure nicotine's metabolites cotinine and 3'-hydroxycotinine and determine CYP2A6 activity (3'-hydroxycotinine/cotinine, i.e. the nicotine metabolite ratio, NMR).The overall frequency of genetically reduced nicotine metabolizers, those with CYP2A6 decrease-of-function or loss-of-function alleles, was lower in the NP compared with the SW (P=0.0006). The CYP2A6 genotype was associated with NMR in both tribal groups (NP, P<0.0001; SW, P=0.04). Notably, the rate of nicotine metabolism was higher in NP compared with SW smokers (P=0.03), and in comparison with other ethnic groups in the USA. Of the variables studied, the CYP2A6 genotype was the only variable to significantly independently influence NMR among smokers in both tribal populations (NP, P<0.001; SW, P=0.05).Unique CYP2A6 allelic patterns and rates of nicotine metabolism among these American Indian populations suggest different risks for smoking, and tobacco-related disease.

SUBMITTER: Tanner JA

PROVIDER: S-EPMC5382092 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer.

Tanner Julie-Anne JA Henderson Jeffrey A JA Buchwald Dedra D Howard Barbara V BV Nez Henderson Patricia P Tyndale Rachel F RF

Pharmacogenetics and genomics 20170501 5

<h4>Objective</h4>The Northern Plains (NP) and Southwest (SW) American Indian populations differ in their smoking patterns and lung cancer incidence. We aimed to compare CYP2A6 genetic variation and CYP2A6 enzyme activity (representative of the rate of nicotine metabolism) between the two tribal populations as these have previously been associated with differences in smoking, quitting, and lung cancer risk.<h4>Participants and methods</h4>American Indians (N=636) were recruited from two differen ...[more]

PMID: 28181923

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Project description:IntroductionGenetic variation in Cytochrome P450 2A6 (CYP2A6), the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations.Aims and methodsAdult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n = 567) or slow (n = 432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. Fagerström test for nicotine dependence scores were measured at baseline and biochemically verified smoking cessation was assessed at end of treatment.ResultsDependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n = 591 European, n = 408 African ancestry) or sex (n = 444 women, n = 555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95 to 1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e. interaction) effect ORs ranged from 0.88 to 1.61 (p = .397-.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high versus low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high versus low dependence had lower quit rates in all three treatment arms.ConclusionsAlthough nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers.ImplicationsVariation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.

Project description:BackgroundAmerican Indians/Alaska Natives have the highest commercial tobacco use in the United States, resulting in higher tobacco-caused deaths and diseases than the general population. Some American Indians/Alaska Natives use commercial tobacco for ceremonial as well as recreational uses. Because federally recognized Tribal lands are sovereign, they are not subject to state cigarette taxes and smoke-free laws. This study analyzes tobacco industry promotional efforts specifically targeting American Indians/Alaska Natives and exploiting Tribal lands to understand appropriate policy responses in light of American Indians'/Alaska Natives' unique sovereign status and culture.MethodsWe analyzed previously secret tobacco industry documents available at the Truth Tobacco Documents Library (https://industrydocuments.library.ucsf.edu/tobacco/).ResultsTobacco companies used promotional strategies targeting American Indians/Alaska Natives and exploiting Tribal lands that leveraged the federally recognized Tribes' unique sovereign status exempting them from state cigarette taxes and smoke-free laws, and exploited some Tribes' existing traditional uses of ceremonial tobacco and poverty. Tactics included price reductions, coupons, giveaways, gaming promotions, charitable contributions, and sponsorships. In addition, tobacco companies built alliances with Tribal leaders to help improve their corporate image, advance ineffective Youth Smoking Prevention programs, and defeat tobacco control policies.ConclusionsThe industry's promotional tactics likely contribute to disparities in smoking prevalence and smoking-related diseases among American Indians//Alaska Natives. Proven policy interventions to address these disparities including tobacco price increases, cigarette taxes, comprehensive smoke-free laws, and industry denormalization campaigns to reduce smoking prevalence and smoking-related disease could be considered by Tribal communities. The sovereign status of federally recognized Tribes does not prevent them from adopting these measures.ImplicationsAmerican Indians/Alaska Natives suffer disparities in smoking prevalence and smoking-related diseases as compared with other groups. The tobacco industry has used promotional tactics including price reductions, coupons and giveaways, casino and bingo promotions, charitable contributions and sponsorships, and so-called Youth Smoking Prevention (YSP) programs to specifically target American Indians/Alaska Natives and exploit Tribal sovereignty, which likely contribute to disparities in tobacco use and related diseases and deaths among this population. Tribal and public health policy makers should consider rejecting ineffective YSP programs and instead consider adopting proven policy interventions including tobacco price increases, cigarette and casino taxes, comprehensive smokefree laws, and anti-industry denormalization campaigns to reduce smoking and smoking-related disease.

Project description:ObjectiveTo study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism.MethodsThe conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes.ResultsThe final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5'-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02).ConclusionAmong European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.

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Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer.

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Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer.

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