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Nicotine metabolism and its association with CYP2A6 genotype among Indigenous people in Alaska who smoke.

ABSTRACT: Prevalence of smoking is higher in Alaska Native and American Indian (ANAI) populations living in Alaska than the general US population. Genetic factors contribute to smoking and cessation rates. The objective of this study was to compare CYP2A6 genetic variation and CYP2A6 enzyme activity toward nicotine in an ANAI population. ANAI (N = 151) people trying to quit smoking were recruited. DNA samples were genotyped for CYP2A6 variants *1X2A, *1B, *2, *4, *9, *10, *12, and *35. Multiple nicotine metabolites were measured in plasma and urine samples, including cotinine and 3'-hydroxycotinine used to determine CYP2A6 activity (e.g., nicotine metabolite ratio [NMR]). We calculated summary statistics for all of the genotypes and metabolites and assigned CYP2A6 activity scores based on known information. We studied the association of CYP2A6 variants with the NMR and smoking histories. The overall frequency of the CYP2A6*1B gain of function allele was high in the ANAI versus non-ANAI populations in other studies. Both *4 null and *9 decrease of function alleles had frequencies similar to previous studies of ANAI populations. In a multivariate analysis, the genotype-inferred CYP2A6 activity score was associated with both plasma and urine NMR (p value = 8.56E-08 and 4.08E-13, respectively). Plasma NMR was also associated with duration of smoking (p value < 0.01) but not urinary total nicotine equivalents uncorrected for creatinine (TNE9_uc ) or biological sex. Urine NMR was significantly associated (p value < 0.01) with TNE9_uc . Variation in NMR in this ANAI population is explained in part by CYP2A6 genetic variation.

SUBMITTER: Schaefer KR

PROVIDER: S-EPMC8604252 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:BackgroundDespite the high prevalence of tobacco use among Alaska Native (AN) people, tobacco cessation interventions developed specifically for this group are lacking. Social media hold promise as a scalable intervention strategy to promote smoking treatment utilization and cessation, given the barriers to treatment delivery (ie, geographic remoteness, limited funding, climate, and travel costs) in the state of Alaska (AK). Building on a longstanding tobacco control research partnership with the AK Tribal Health System, in this study, we are developing and pilot-testing a culturally relevant, Facebook (FB)-delivered intervention that incorporates a digital storytelling approach adapted from the effective Centers for Disease Control Tips from Former Smokers campaign.ObjectiveThis study aims to promote evidence-based smoking treatment (eg, state quitline and Tribal cessation programs) uptake and cessation among AN people.MethodsThis study fulfills the objectives for stage 1 of the National Institute on Drug Abuse behavioral integrative treatment development program. In stage 1a, we will use a mixed method approach to develop the FB intervention. Cultural variance and surface/deep structure frameworks will address the influence of culture in designing health messages. These developmental activities will include qualitative and quantitative assessments, followed by beta testing of proposed intervention content. In stage 1b, we will conduct a randomized pilot trial enrolling 60 AN adults who smoke. We will evaluate the feasibility, uptake, consumer response, and potential efficacy of the FB intervention compared with a control condition (quitline/treatment referral only). Primary outcome measures include feasibility and biochemically verified smoking abstinence at 1-, 3-, and 6-month follow-ups. Secondary outcomes will include self-reported smoking cessation treatment utilization and abstinence from tobacco/nicotine products. We will also explore interdependence (relationship orientation and collaborative efforts in lifestyle change) as a culturally relevant mediator of intervention efficacy.ResultsThe study enrolled 40 participants for phase 1, with data saturation being achieved at 30 AN people who smoke and 10 stakeholders. For phase 2, we enrolled 40 participants. Qualitative assessment of proposed intervention content was completed with 30 AN smokers and 10 stakeholders. We are currently analyzing data from the quantitative assessment with 40 participants in preparation for the beta testing, followed by the randomized pilot trial.ConclusionsThe project is innovative for its use of social media communication tools that are culturally relevant in a behavioral intervention designed to reach AN people statewide to promote smoking treatment utilization and cessation. The study will further advance tobacco cessation research in an underserved disparity group. If the pilot intervention is successful, we will have a blueprint to conduct a large randomized controlled efficacy trial. Our approach could be considered for other remote AN communities to enhance the reach of evidence-based tobacco cessation treatments.International registered report identifier (irrid)DERR1-10.2196/15155.

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Nicotine metabolism and its association with CYP2A6 genotype among Indigenous people in Alaska who smoke.

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