PharmVar GeneFocus: CYP2A6.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the human CYP2A gene locus containing the highly polymorphic CYP2A6 gene. CYP2A6 plays a role in the metabolism of nicotine and various drugs. Thus, genetic variation can substantially contribute to the function of this enzyme and associated efficacy and safety.

Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline.

Varenicline, the most efficacious smoking cessation monotherapy, produces abnormal dreams. Although genetic contributions to varenicline-associated nausea and cessation have been identified, the role of genetics in abnormal dreams is unknown. We conducted a genomewide association study (GWAS) of abnormal dreams in 188 European ancestry smokers treated with varenicline (NCT01314001).

Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension.

CYP2A6 is a polymorphic enzyme that inactivates nicotine; structural variants (SVs) include gene deletions and hybrids with the neighboring pseudogene CYP2A7. Two studies found that CYP2A7 deletions were associated with ovarian cancer risk. Using their methodology, we aimed to characterize CYP2A6 SVs (which may be misidentified by prediction software as CYP2A7 SVs), then assess CYP2A6 SV-associated risk for ovarian cancer, and extend analyses to lung cancer.

Pharmacogenetics of Biochemically Verified Abstinence in an Opioid Agonist Therapy Randomized Clinical Trial of Methadone and Buprenorphine/Naloxone.

Methadone and buprenorphine/naloxone are opioid agonist therapies for opioid use disorder treatment. Genetic factors contribute to individual differences in opioid response; however, little is known regarding genetic associations with clinical outcomes in people receiving opioid agonist therapies. Participants diagnosed with opioid use disorder, principally consisting of prescription opioids (licit or illicit), were randomized to methadone or buprenorphine/naloxone for 24 weeks of daily treatment (NCT03033732).

A Multisite Electronic Health Record Integrated Remote Monitoring Intervention for Hypertension Improvement: Protocol for a Randomized Pragmatic Comparative Effectiveness Trial.

Background: Hypertension is a major contributor to various adverse health outcomes. Although previous studies have shown the benefits of home blood pressure (BP) monitoring over office-based measurements, there is limited evidence comparing the effectiveness of whether a BP monitor integrated into the electronic health record is superior to a nonintegrated BP monitor.

Objective: In this paper, we describe the protocol for a pragmatic multisite implementation of a quality improvement initiative directly comparing integrated to nonintegrated BP monitors for hypertension improvement.

CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study.

CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887).

Repetitive transcranial magnetic stimulation for smoking cessation: Next steps for translation and implementation into clinical practice.

Tobacco smoking is a significant determinant of preventable morbidity and mortality worldwide. It is now possible to modulate the activity of the neurocircuitry associated with nicotine dependence using repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neurostimulation approach, which has recently demonstrated efficacy in clinical trials and received regulatory approval in the US and Canada. However there remains a paucity of replication studies and real-world patient effectiveness data as access to this intervention is extremely limited.

Influence of CYP2A6 Genetic Variation, Nicotine Dependence Severity, and Treatment on Smoking Cessation Success.

Introduction: Genetic 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.

Genetic variation in fatty acid amide hydrolase (FAAH): Associations with early drinking and smoking behaviors.

Background: The endocannabinoid system is implicated in psychiatric disorders and drug dependence. Within this system, fatty acid amide hydrolase (FAAH) metabolizes endocannabinoids. Individuals with A-group genotypes (C/A or A/A) of a common FAAH variant (rs324420; C > A; Pro129Thr) have slower enzymatic activity compared to C-group individuals (C/C genotype).

Does genetic variation in a bitter taste receptor gene alter early smoking behaviours in adolescents and young adults?

Background And Aims: Variation in the TAS2R38 taste receptor gene alters the ability to taste bitter compounds. We tested whether TAS2R38 variation influences early smoking behaviours in adolescence, a critical period of acquisition when taste may influence the natural course of tobacco use.

Design And Participants: Observational study (Nicotine Dependence in Teens [NDIT]).

Examining the role of mitochondrial genetic variation in nicotine dependence.

Nicotine dependence (ND) has a heritability rate of ∼50%, suggesting genetic factors contribute to underlying mechanisms. Here, we aimed to examine variants within both mtDNA and the nuclear genome to determine if mitochondrial genes are associated with ND. A total of 129 mtDNA SNPs and 1136 nuclear-encoded mitochondrial genes in a sample of N = 374 Caucasians were selected for analysis.

Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes.

Objectives: We evaluated multiple genotyping/sequencing approaches in a homologous region of chromosome 19, and investigated associations of two common 3'-UTR CYP2A6 variants with activity in vivo.

Methods: Individuals (n = 1704) of European and African ancestry were phenotyped for the nicotine metabolite ratio (NMR), an index of CYP2A6 activity, and genotyped/sequenced using deep amplicon exon sequencing, SNP array, genotype imputation and targeted capture sequencing. Amplicon exon sequencing was the gold standard to which other methods were compared within-individual for CYP2A6, CYP2A7, CYP2A13, and CYP2B6 exons to identify highly discordant positions.

Does sex alter the relationship between CYP2B6 variation, hydroxybupropion concentration and bupropion-aided smoking cessation in African Americans? A moderated mediation analysis.

Background And Aims: CYP2B6, a genetically variable enzyme, converts bupropion to its active metabolite hydroxybupropion. CYP2B6 activity and bupropion-aided cessation differ between women and men. The aim of this study was to determine whether genetically normal (versus reduced) CYP2B6 activity increases bupropion-aided cessation in African American smokers via higher hydroxybupropion concentration, and whether this differs by sex.

Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans.

Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3'hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3'hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978).

Stability of Varenicline Concentration in Saliva Over 21 Days at Three Storage Temperatures.

Introduction: Varenicline is the most efficacious drug for smoking cessation; saliva varenicline concentrations can be useful for the evaluation of adherence in smoking cessation trials. Saliva is a useful noninvasive matrix for mail-in specimen collection, if stable. We investigated the stability of varenicline in saliva at different storage temperatures simulating the time it takes to mail in a sample.

Nicotine metabolite ratio: Comparison of the three urinary versions to the plasma version and nicotine clearance in three clinical studies.

Background: Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3'-hydroxycotinine to free cotinine (NMR), total trans-3'-hydroxycotinine to free cotinine (NMR), or total trans-3'-hydroxycotinine to total cotinine (NMR).

Impact of CYP2A6 Activity on Nicotine Reinforcement and Cue-Reactivity in Daily Smokers.

Introduction: Variation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated.

Aims And Methods: CYP2A6 activity was indexed using 3 genetic approaches in 104 daily smokers completing forced-choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively.

A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers.

Introduction: Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood.

Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations.

The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation.

KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: A systematic literature review and meta-analysis.

KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation detected in patients with non-small cell lung cancer (NSCLC). However, the role of KRAS as either a prognostic factor or predictive factor (modifier of treatment effects) in NSCLC is not well established at this time. This systematic literature review (SLR) and meta-analysis synthesized the available evidence regarding the role of KRAS mutation as a predictive factor and/or prognostic factor of survival and response outcomes in patients with advanced/metastatic (stage IIIB-IV) NSCLC.

Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent.

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3'hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers.