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1.  CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska-Native tobacco users 
Addiction (Abingdon, England)  2013;108(10):1818-1828.
Background and aims
Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and β4 nicotinic receptor subunits, are associated with altered smoking behaviors in European-Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska-Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use, and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska-Native people.
Design, Setting, Participants
A cross sectional study of 400 Alaska-Native individuals including 290 tobacco users.
Measurements
CHRNA5-A3-B4 genotype, body weight, and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE).
Findings
Alaska-Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African-Americans. In 290 Alaska-Native tobacco users, the ‘G’ allele of rs578776, which tagged a 30kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and significantly associated with nicotine intake (20% higher plasma cotinine, P<0.001, 16% higher TNE, P=0.076), while rs16969968 was not associated with nicotine intake. Rs578776 acted in combination with CYP2A6, the main nicotine-metabolizing enzyme, to increase nicotine intake by 1.8 fold compared with the low risk group (P<0.001). Furthermore rs2869950, a single nucleotide polymorphism 5′ to CHRNB4, was significantly associated with increased body mass index (P<0.01) in the tobacco users even after controlling for differences in nicotine intake (P<0.01).
Conclusions
Genetic variants in CHRNA5-A3-B4 alter nicotine intake and body mass index in a population of Alaska-Native people, who have a distinct haplotype structure, smoking behaviors and prevalence of obesity.
doi:10.1111/add.12250
PMCID: PMC3775934  PMID: 23692359
Alaska-Native People; Smoking; CHRNA5-A3-B4; Obesity
2.  First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo 
Biochemical pharmacology  2013;85(12):1848-1855.
The response to centrally-acting drugs is highly variable between individuals and does not always correlate with plasma drug levels. Drug-metabolizing CYP enzymes in the brain may contribute to this variability by affecting local drug and metabolite concentrations. CYP2D metabolizes codeine to the active morphine metabolite. We investigate the effect of inhibiting brain, and not liver, CYP2D activity on codeine-induced analgesia. Rats received intracerebroventricular injections of CYP2D inhibitors (20 μg propranolol or 40 μg propafenone) or vehicle controls. Compared to vehicle-pretreated rats, inhibitor-pretreated rats had: a) lower analgesia in the tail-flick test (p<0.05) and lower areas under the analgesia-time curve (p<0.02) within the first hour after 30 mg/kg subcutaneous codeine, b) lower morphine concentrations and morphine to codeine ratios in the brain (p<0.02 and p<0.05, respectively), but not in plasma (p>0.6 and p>0.7, respectively), tested at 30 min after 30 mg/kg subcutaneous codeine, and c) lower morphine formation from codeine ex vivo by brain membranes (p<0.04), but not by liver microsomes (p>0.9). Analgesia trended toward a correlation with brain morphine concentrations (p=0.07) and correlated with brain morphine to codeine ratios (p<0.005), but not with plasma morphine concentrations (p>0.8) or plasma morphine to codeine ratios (p>0.8). Our findings suggest that brain CYP2D affects brain morphine levels after peripheral codeine administration, and may thereby alter codeine's therapeutic efficacy, side-effect profile and abuse liability. Brain CYPs are highly variable due to genetics, environmental factors and age, and may therefore contribute to interindividual variation in the response to centrally-acting drugs.
doi:10.1016/j.bcp.2013.04.014
PMCID: PMC3687523  PMID: 23623752
cytochrome P450; codeine; analgesia; drug metabolism; pharmacokinetics; neuropharmacology
3.  The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex 
Background
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure.
Methods
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163).
Results
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males.
Conclusions
In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.
Impact
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
doi:10.1158/1055-9965.EPI-12-1234-T
PMCID: PMC3617060  PMID: 23371292
Tobacco; Cotinine; CYP2A6; Polycyclic aromatic hydrocarbons; NNAL
4.  CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers 
Pharmacogenetics and genomics  2013;23(4):232-235.
Variation in the CYP2A6 gene, that decreases the rate of nicotine metabolic-inactivation, is associated with higher adult smoking cessation rates during clinical trials. We hypothesized that slow metabolism is associated with increased quitting during adolescence. Caucasian adolescent smokers (N=308, aged 12 to 17, 36.3% male) from a cohort study were genotyped for CYP2A6 resulting in 7.8% slow, 14.0% intermediate and 78.2% normal metabolizers. Overall, 144 smokers quit smoking, as indicated by being abstinent for ≥12 months. In logistic regression analyses, the odds ratio for quitting was 2.25 (95% confidence interval 1.05, 4.80; P=0.037) for slow metabolizers relative to normal metabolizers. A linear trend toward increased quitting with decreasing CYP2A6 activity was also observed (odds ratio = 1.44, 95% confidence interval 1.02, 2.01; P=0.034). Thus, CYP2A6 slow metabolism is associated with increased adolescent smoking cessation, indicating that even early in the smoking history genetic variation is influencing smoking cessation.
doi:10.1097/FPC.0b013e32835f834d
PMCID: PMC3744214  PMID: 23462429
adolescent; longitudinal studies; epidemiology; smoking cessation; genetic association studies
5.  CYP2B6 and bupropion’s smoking cessation pharmacology: the role of hydroxybupropion 
Bupropion is indicated to promote smoking cessation. Animal studies suggest that bupropion’s major metabolite hydroxybupropion can mediate bupropion’s pharmacologic activity. We measured plasma bupropion and metabolite levels in a double-blind, placebo controlled, randomized smoking cessation trial. Among the treatment adherent individuals, higher hydroxybupropion concentrations (per µg/mL) resulted in better smoking cessation outcomes (Week 3, 7 and 26 OR=2.82, 2.96 and 2.37, P=0.005–0.040), this was not observed with bupropion levels (OR=1.00–1.03, P=0.59–0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6-mediated hydroxybupropion formation. These findings suggest dosing bupropion to achieve a hydroxybupropion level of 0.7 µg/ml or increasing bupropion dose for CYP2B6 slow metabolizers, could improve bupropion’s cessation outcomes.
doi:10.1038/clpt.2012.186
PMCID: PMC3729209  PMID: 23149928
6.  Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor 
Nicotine & Tobacco Research  2013;16(1):18-25.
Introduction:
The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years.
Methods:
Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration.
Results:
Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine’s Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively. Additionally, methoxsalen potentiated nicotine-induced antinociception and hypothermia as evidenced by leftward shifts in nicotine’s dose–response curve. Furthermore, this prolongation of nicotine’s effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter pharmacological effects of nicotine given orally.
Conclusion:
We have shown that the pharmacological effects of inhibiting nicotine’s metabolism after oral administration in mice are profound. Our results suggest that inhibiting nicotine metabolism can be used to dramatically enhance nicotine’s bioavailability and its resulting pharmacology, which further supports this inhibitory approach for clinical development of an oral nicotine replacement therapy.
doi:10.1093/ntr/ntt105
PMCID: PMC3864487  PMID: 23884323
7.  Variation in Trans-3′-Hydroxycotinine Glucuronidation Does Not Alter the Nicotine Metabolite Ratio or Nicotine Intake 
PLoS ONE  2013;8(8):e70938.
Background
CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the “nicotine metabolite ratio”, NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility.
Methods
Plasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped.
Results
The UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking.
Conclusions
Variation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism.
doi:10.1371/journal.pone.0070938
PMCID: PMC3732272  PMID: 23936477
8.  Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers 
CYP2A6 is the main nicotine metabolizing enzyme in humans. We investigated the relationships between CYP2A6 genotype, baseline plasma 3HC/COT (a phenotypic marker of CYP2A6 activity), and smoking behaviors in African-American light smokers. Cigarette consumption, age of initiation, and dependence scores did not differ between 3HC/COT quartiles or CYP2A6 genotype groups. Slow metabolizers (both genetic and phenotypic) had significantly higher plasma nicotine levels suggesting cigarette consumption was not reduced to adjust for slower rates of nicotine metabolism. Individuals in the slowest 3HC/COT quartile had higher quit rates with both placebo and nicotine gum treatments (OR 1.85, 95% CI 1.08-3.16, p = 0.03). Similarly, the slowest CYP2A6 genotype group had higher quit rates, although this did not reach significance (OR 1.61, 95% CI 0.95-2.72, p = 0.08). 3HC/COT ratio, and possibly CYP2A6 genotype, may be useful in the future for personalizing the choice of smoking cessation treatment for African-American light smokers.
doi:10.1038/clpt.2009.19
PMCID: PMC3698861  PMID: 19279561
Cytochrome P450 2A6; CYP2A6; nicotine; cotinine; trans-3′-hydroxycotinine; African-Americans; smoking; light smokers
9.  Factors Associated with Discontinuation of Bupropion and Counseling among African American Light Smokers in a Randomized Clinical Trial 
Background
African Americans are at risk for inadequate adherence to smoking cessation treatment yet little is known about what leads to treatment discontinuation.
Purpose
Examine the factors associated with discontinuation of treatment in African American light smokers (≤10 cigarettes per day).
Methods
Bupropion plasma levels and counseling attendance were measured among 540 African American light smokers in a placebo-controlled randomized trial of bupropion.
Results
By Week 3, 28.0% of subjects in the bupropion arm had discontinued bupropion and only moderate associations were found between plasma levels and self-reported bupropion use (rs=0.38). By Week 16, 36.9% of all subjects had discontinued counseling. Males had greater odds of discontinuing medication (OR=2.02, 95% CI, 1.10–3.71, p=0.02) and older adults had lower odds of discontinuing counseling (OR=0.96, 95% CI, 0.94–0.97, p<0.0001).
Conclusions
Bupropion and smoking cessation counseling are underutilized even when provided within the context of a randomized trial. Future research is needed to examine strategies for improving treatment utilization among African American smokers.
doi:10.1007/s12160-013-9510-x
PMCID: PMC3815499  PMID: 23733379
Smoking cessation; discontinuation of treatment; African Americans
10.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
Aims
To evaluate associations of treatment and an ‘additive genetic efficacy score’ (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled in two randomized clinical trials of smoking cessation therapies.
Design
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.
Setting
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
Participants
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Measurements
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Findings
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (HR = 1.29, 95%CI 1.17–1.41, p=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
Conclusions
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
doi:10.1111/add.12325
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
11.  CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people 
Pharmacogenetics and Genomics  2012;22(6):429-440.
Objectives
Alaska Native people (AN) have a high prevalence of tobacco use and associated morbidity and mortality when compared to the general U.S. population. Variation in the CYP2A6 and CYP2B6 genes, encoding enzymes responsible for nicotine metabolic inactivation and procarcinogen activation, has not been characterized in AN and may contribute to the increased risk.
Methods
AN people (n = 400) residing in the Bristol Bay region of South Western Alaska were recruited for a cross-sectional study on tobacco use. They were genotyped for CYP2A6*1X2A, *1X2B, *1B, *2, *4, *7, *8, *9, *10, *12, *17, *35 and CYP2B6*4, *6, *9 and provided plasma and urine samples for measurement of nicotine and metabolites.
Results
CYP2A6 and CYP2B6 variant frequencies among the AN Yupik people (n=361) were significantly different from other ethnicities. Nicotine metabolism (as measured by the plasma and urinary ratio of metabolites trans-3’hydroxycotinine to cotinine [(3HC/COT)] was significantly associated with CYP2A6 (P< 0.001) but not CYP2B6 genotype (P = 0.95) when controlling for known covariates. Of note, plasma 3HC/COT ratios were high in the entire Yupik people, and among the Yupik CYP2A6 wild-type participants they were substantially higher than previously characterized racial/ethnic groups (P < 0.001 vs. Caucasians and African Americans).
Conclusions
Yupik AN people have a unique CYP2A6 genetic profile which associated strongly with in vivo nicotine metabolism. More rapid CYP2A6-mediated nicotine and nitrosamine metabolism in the Yupik people may modulate tobacco-related disease risk.
doi:10.1097/FPC.0b013e3283527c1c
PMCID: PMC3349071  PMID: 22569203
CYP2A6; CYP2B6; nicotine; tobacco; smoking; genetic variation; Alaska Native people
12.  Neuroimaging in Psychiatric Pharmacogenetics Research: The Promise and Pitfalls 
Neuropsychopharmacology  2013;38(12):2327-2337.
The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype × drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment.
doi:10.1038/npp.2013.152
PMCID: PMC3799069  PMID: 23793356
imaging; clinical or preclinical; neurogenetics; neuroimaging; neuropharmacology; pharmacogenetics/pharmacogenomics; psychiatry; treatment; neuroimaging; pharmacogenetics; psychiatry; treatment
13.  Potential role of CYP2D6 in the central nervous system 
Cytochrome P450 2D6 (CYP2D6) is a pivotal enzyme responsible for a major human drug oxidation polymorphism in human populations. Distribution of CYP2D6 in brain and its role in serotonin metabolism suggest this CYP2D6 may have a function in central nervous system.To establish an efficient and accurate platform for the study of CYP2D6 in vivo, a transgenic human CYP2D6 (Tg-2D6) model was generated by transgenesis in wild-type C57BL/6 (WT) mice using a P1 phage artificial chromosome clone containing the complete human CYP2D locus, including CYP2D6 gene and 5’- and 3’- flanking sequences.Human CYP2D6 was expressed not only in the liver, but also in brain. The abundance of serotonin and 5-hydroxyindoleacetic acid in brain of Tg-2D6 is higher than in WT mice either basal levels or after harmaline induction. Metabolomics of brain homogenate and cerebrospinal fluid revealed a significant up-regulation of l-carnitine, acetyl-l-carnitine, pantothenic acid, dCDP, anandamide, N-acetylglucosaminylamine, and a down-regulation of stearoyl-l-carnitine in Tg-2D6 mice compared with WT mice. Anxiety tests indicate Tg-2D6 mice have a higher capability to adapt to anxiety.Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable in vivo tool to determine CYP2D6-involved neurophysiological metabolism and function.
doi:10.3109/00498254.2013.791410
PMCID: PMC3750078  PMID: 23614566
CYP2D6; brain; serotonin; anxiety
14.  Relationship Between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 Variation and Smoking Behaviors and Lung Cancer Risk 
Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal–Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.
doi:10.1093/jnci/djr237
PMCID: PMC3168937  PMID: 21747048
15.  Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers 
Background
Cigarette smoking is an important risk factor for abdominal obesity. However, the degree to which the CYP2A6 genotype moderates the relationship between smoking and abdominal obesity has not been established.
Purpose
This study aims to investigate whether or not the relationship between smoking quantity and abdominal obesity is influenced by CYP2A6 genotypes.
Methods
Nine hundred fifty-four male current smokers were selected. A venous specimen was collected to test serum cotinine and CYP2A6 genotype, and all smokers were divided into heavy (>15 cigarettes/day) and light smokers (≤15 cigarettes/day).
Results
Heavy smoking increased the risk of abdominal obesity (odds ratio (OR)=1.57; 95% CI, 1.13–2.19) compared with light smoking. Furthermore, heavy smoking had a positive interactive effect with CYP2A6 poor metabolizer genotype on abdominal obesity (OR=3.90; 95% CI, 1.25– 12.18). Moreover, CYP2A6 poor metabolizer genotypes were associated with slower nicotine metabolism.
Conclusions
Heavy smoking may increase the risk of abdominal obesity—particularly in smokers with CYP2A6 poor metabolizer genotypes.
doi:10.1007/s12160-011-9318-5
PMCID: PMC4114962  PMID: 22160797
Cigarette smoking; CYP2A6 genotypes; Abdominal obesity; Interaction
16.  Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways 
Objective
To explore the interactions between smoking and CYP2A6 genotypes on type 2 diabetes (T2DM) as well as potential pathways for smoking in causing T2DM.
Design
Cross-sectional study.
Methods
A total of 1344 smokers with complete data from a community-based T2DM survey in Guangzhou and Zhuhai of China from July 2006 to June 2007 were interviewed with a structured questionnaire about socio-demographic status and daily cigarette consumption. Serum glucose, insulin, and cotinine were measured after an overnight fast. Subjects were genotyped for CYP2A6 and classified, according to genotype, into normal, intermediate, slow, or poor nicotine metabolizers based on prior knowledge of CYP2A6 allele associations with nicotine C-oxidation rate. Abdominal obesity was defined as a waist-to-hip ratio ≥0.90 for males or ≥0.85 for females. Type 2 diabetic patients (n=154) were diagnosed according to WHO 1999 criteria. Chi-square tests, multivariate logistic regression models, and a structural equation model were used in this study.
Results
Multivariate analysis indicated that, compared with light smoking, heavy smoking significantly increased the risk of T2DM (odds ratio (OR)=1.75, 95% CI=1.01–3.05). There were significant interactions between heavy smoking and slow CYP2A6 (OR=5.12, 95% CI=1.08–24.23) and poor CYP2A6 metabolizer genotypes (OR=8.54, 95% CI=1.28–57.02) on T2DM. Structural equation modeling indicated that CYP2A6 moderation of smoking quantity risk on T2DM was mediated by the effects on serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.
Conclusions
Heavy smoking was significantly associated with T2DM, and this association was moderated by CYP2A6 genotype and mediated by serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.
doi:10.1530/EJE-11-0596
PMCID: PMC4112659  PMID: 21964962
17.  The DRD4 Exon III VNTR, Bupropion, and Associations With Prospective Abstinence 
Nicotine & Tobacco Research  2012;15(7):1190-1200.
Introduction:
DRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive–behavioral mood management therapy.
Methods:
We used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies. VNTR genotypes were coded with the long allele dominant resulting in 4 analysis categories. Covariates included demographics, dependence measures, depressive symptoms, and genetic ancestry. We also performed genotype-stratified secondary analyses.
Results:
We observed significant effects of time in longitudinal analyses of both abstinence outcomes, of treatment in individuals with VNTR long allele genotypes for both abstinence outcomes, and of covariates in some analyses. We observed non-significantly larger differences in active versus placebo effect sizes in individuals with VNTR long allele genotypes than in individuals without the VNTR long allele, in the directions previously reported.
Conclusions:
VNTR by treatment interaction differences between these and previous analyses may be attributable to insufficient size of the replication sample. Analyses of multiple randomized clinical trials will enable identification and validation of factors mediating treatment response.
doi:10.1093/ntr/nts245
PMCID: PMC3682839  PMID: 23212438
18.  Utility and relationships of biomarkers of smoking in African-American light smokers 
While expired carbon monoxide (CO) and plasma cotinine (COT) have been validated as biomarkers of self-reported cigarettes per day (CPD) in heavy smoking Caucasians, their utility in light smokers is unknown. Further, variability in CYP2A6, the enzyme that mediates formation of COT from nicotine (NIC) and its metabolism to trans-3′-hydroxycotinine (3HC), may limit the usefulness of COT. We assessed whether CO and COT are correlated with CPD in African-American light smokers (≤10CPD, n=700), a population with known reduced CYP2A6 activity and slow COT metabolism. We also examined whether gender, age, BMI, smoking mentholated cigarettes or rate of CYP2A6 activity, by genotype and phenotype measures (3HC/COT), influence these relationships. At baseline, many participants (42%) exhaled CO ≤10ppm, the traditional cutoff for smoking, while few (3.1%) had COT below the cutoff of ≤14ng/ml; thus COT appears to be a better biomarker of smoking status in this population. CPD was weakly correlated with CO and COT (r = 0.32–0.39, p<0.001), and those reporting fewer CPD had higher CO/cigarette and COT/cigarette, although the correlations coefficients between these variables were also weak (r = −0.33 and −0.08, p < 0.05). The correlation between CPD and CO was not greatly increased when analyzed by CYP2A6 activity, smoking mentholated cigarettes or age, although it appeared stronger in females (r = 0.38 vs.0.21, p<0.05) and obese individuals (r = 0.38 vs.0.24, p<0.05). Together, these results suggest that CO and COT are weakly associated with self-reported cigarette consumption in African-American light smokers, and that these relationships are not substantially improved when variables previously reported to influence these biomarkers are considered.
doi:10.1158/1055-9965.EPI-09-0956
PMCID: PMC2791893  PMID: 19959692
biomarkers; smoking; cotinine; carbon monoxide; African-Americans
19.  Pharmacogenetics: A Tool for Identifying Genetic Factors in Drug Dependence and Response to Treatment 
Pharmacogenetics research looks at variations in the human genome and ways in which genetic factors might influence how individuals respond to drugs. The authors review basic principles of pharmacogenetics and cite findings from several gene-phenotype studies to illustrate possible associations between genetic variants, drug-related behaviors, and risk for drug dependence. Some gene variants affect responses to one drug; others, to various drugs. Pharmacogenetics can inform medication development and personalized treatment strategies; challenges lie along the pathway to its general use in clinical practice.
PMCID: PMC3120126  PMID: 22002450
20.  Genetic and Pharmacokinetic Determinants of Response to Transdermal Nicotine in White, Black and Asian Non-Smokers 
Clinical pharmacology and therapeutics  2013;94(6):10.1038/clpt.2013.159.
The aim of the study was to examine genetic, pharmacokinetic and demographic factors that influence sensitivity to nicotine in never smokers. Sixty never smokers, balanced for gender and race (Caucasian, Blacks and Asian), wore 7 mg nicotine skin patches for up to 8 hours. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in 9 subjects and was strongly associated with rate of rise and peak concentrations of plasma nicotine. Toxicity, subjective and cardiovascular effects of nicotine were associated with the presence of reduced function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when the latter are used for treating medical conditions in non-smokers, and possibly in vulnerability to developing nicotine dependence.
doi:10.1038/clpt.2013.159
PMCID: PMC3834081  PMID: 23933970
21.  A novel CYP2A6 allele (CYP2A6*35) resulting in an amino acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo 
The pharmacogenomics journal  2009;9(4):274-282.
Cytochrome P450 2A6 (CYP2A6) is the primary human enzyme involved in nicotine metabolism. Our objective was to characterize two nonsynonymous single nucleotide polymorphisms (SNPs) in CYP2A6*24, 594G>C (Val110Leu) and 6458A>T (Asn438Tyr). We determined their haplotype, allele frequencies, effect on CYP2A6 activity in vivo, as well as their stability and ability to metabolize nicotine in vitro. CYP2A6*35 (6458A>T) occurred at a frequency of 2.5–2.9% among individuals of black African descent, 0.5–0.8% among Asians, and was not found in Caucasians. In addition, we identified two novel alleles, CYP2A6*36 (6458A>T and 6558T>C [Ile471Thr]) and CYP2A6*37 (6458A>T, 6558T>C, and 6600G>T [Arg485Leu]). In vivo, CYP2A6*35 was associated with lower CYP2A6 activity as measured by the 3HC/COT ratio. In vitro, CYP2A6.35 had decreased nicotine C-oxidation activity and thermal stability. In conclusion, we identified three novel CYP2A6 alleles (CYP2A6*35, *36, and *37); the higher allele frequency variant CYP2A6*35 was associated with lower CYP2A6 activity.
doi:10.1038/tpj.2009.11
PMCID: PMC2922203  PMID: 19365400 CAMSID: cams1468
Nicotine; Cotinine; CYP2A6; Smoking; Pharmacogenetics
22.  Identification of novel CYP2A6*1B variants; the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism 
Background
Cytochrome P450 2A6 (CYP2A6) is the human enzyme responsible for the majority of nicotine’s metabolism. CYP2A6 genetic variants contribute to the inter-individual and inter-ethnic variation in nicotine metabolism. We examined the association between the CYP2A6*1B variant and nicotine’s in vivo metabolism.
Methods
Intravenous infusions of deuterium-labeled nicotine were administered to 292 volunteers, 163 of whom were White and did not have common CYP2A6 variants, other than CYP2A6*1B.
Results
We discovered three novel CYP2A6*1B variants in the 3′-flanking region of the gene that can confound genotyping assays. We found significant differences between CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B groups in total nicotine clearance (17.2±5.2, 19.0±6.4 and 20.4±5.9, P < 0.02), nonrenal nicotine clearance (16.4±5.0, 18.5±6.2 and 19.8±5.7, P < 0.01) and the plasma 3HC/COT ratio (0.26±0.1, 0.26±0.1 and 0.34±0.1, P < 0.001). There were also differences in total nicotine (29.4±12.9, 25.8±0.12.9 and 22.4±12.4, P < 0.01), cotinine (29.2±8.1, 32.2±9.1 and 33.0±6.6, P < 0.01) and trans-3′-hydroxcotinine (32.4±9.1, 34.2±12.3 and 41.3±11.3, P < 0.001) excreted in the urine.
Conclusion
We report evidence that CYP2A6*1B genotype is associated with faster nicotine clearance in vivo, which will be important to future CYP2A6 genotype association studies.
doi:10.1038/sj.clpt.6100246
PMCID: PMC2921956  PMID: 17522595 CAMSID: cams1335
23.  Utility and relationships of biomarkers of smoking in African-American light smokers 
While expired carbon monoxide (CO) and plasma cotinine (COT) have been validated as biomarkers of self-reported cigarettes per day (CPD) in heavy smoking Caucasians, their utility in light smokers is unknown. Further, variability in CYP2A6, the enzyme that mediates formation of COT from nicotine (NIC) and its metabolism to trans-3′-hydroxycotinine (3HC), may limit the usefulness of COT. We assessed whether CO and COT are correlated with CPD in African-American light smokers (≤10CPD, n=700), a population with known reduced CYP2A6 activity and slow COT metabolism. We also examined whether gender, age, BMI, smoking mentholated cigarettes or rate of CYP2A6 activity, by genotype and phenotype measures (3HC/COT), influence these relationships. At baseline, many participants (42%) exhaled CO ≤10ppm, the traditional cutoff for smoking, while few (3.1%) had COT below the cutoff of ≤14ng/ml; thus COT appears to be a better biomarker of smoking status in this population. CPD was weakly correlated with CO and COT (r = 0.32–0.39, p<0.001), and those reporting fewer CPD had higher CO/cigarette and COT/cigarette, although the correlations coefficients between these variables were also weak (r = −0.33 and −0.08, p < 0.05). The correlation between CPD and CO was not greatly increased when analyzed by CYP2A6 activity, smoking mentholated cigarettes or age, although it appeared stronger in females (r = 0.38 vs.0.21, p<0.05) and obese individuals (r = 0.38 vs.0.24, p<0.05). Together, these results suggest that CO and COT are weakly associated with self-reported cigarette consumption in African-American light smokers, and that these relationships are not substantially improved when variables previously reported to influence these biomarkers are considered.
doi:10.1158/1055-9965.EPI-09-0956
PMCID: PMC2791893  PMID: 19959692 CAMSID: cams1333
biomarkers; smoking; cotinine; carbon monoxide; African-Americans
24.  A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent 
Pharmacogenetics and genomics  2008;18(1):67-75.
Objectives
CYP2A6 is the main enzyme involved in nicotine metabolism in humans. We have identified a novel allele, CYP2A6*23 (2161C>T, R203C), in individuals of Black-African descent and investigated its impact on enzyme activity and association with smoking status.
Methods
Wildtype and variant enzymes containing amino acid changes R203C (CYP2A6*23), R203S (CYP2A6*16) and V365M (CYP2A6*17) were expressed in Escherichia coli. The effect of CYP2A6*23 in vivo was examined in individuals of Black-African descent given 4 mg oral nicotine.
Results
CYP2A6*23 occurred at an allele frequency of 2.0% in individuals of Black-African descent (N = 560 alleles, 95% confidence interval 0.8%–3.1%) and was not detected in Caucasians (N = 334 alleles), Chinese (N = 288 alleles) or Japanese (N = 104 alleles). In vitro, CYP2A6.23 had greatly reduced activity towards nicotine C-oxidation similar to CYP2A6.17, as well as reduced coumarin 7-hydroxylation. Conversely, CYP2A6.16 did not differ in activity compared to the wildtype enzyme. The trans-3′-hydroxycotinine to cotinine ratio, a phenotypic measure of CYP2A6 activity in vivo, was lower in CYP2A6*1/*23 and CYP2A6*23/*23 individuals(mean adjusted ratio of 0.60, n = 5) compared to CYP2A6*1/*1 individuals (mean adjusted ratio of 1.21, n = 150) (p < 0.04). CYP2A6*23 trended towards a higher allele frequency in nonsmokers (3.1%, N = 9/286 alleles) compared to smokers (0.7%, N = 2/274 alleles) (p = 0.06).
Conclusions
These results suggest the novel CYP2A6*23 allele impairs enzyme function in vitro and in vivo and trends toward an association with lower risk of smoking.
doi:10.1097/FPC.0b013e3282f3606e
PMCID: PMC2910083  PMID: 18216723 CAMSID: cams1332
CYP2A6; genetic polymorphisms; Black-Africans; nicotine; smoking
25.  Socioeconomic and drug use determinants of smoking status in a Canadian urban adult population of black African descent 
Our aim was to examine the influence that socioeconomics and drug use had on current smokers (n=137) and nonsmokers (n=143) from an urban adult population of black African descent. Participants were a median of 33 years (range 20–59). Smokers consumed a median of 8 cigarettes per day (range 0–35). Interestingly, 86% smoked <15 cigarettes per day and only 8% smoked menthol cigarettes. Socioeconomic and drug use variables that were significantly associated with smoking status in univariate analyses were included in a multiple logistic regression model that controlled for gender and age. Compared to nonsmokers, smokers were less likely to be university educated (adjusted odds ratio (AOR)=0.08 [95% CI: 0.02–0.43]), more likely to be divorced/separated/widowed (AOR=10.3 [2.8–37.6]), more likely to be current alcohol users (AOR=3.5 [1.8–7.0]) and more likely to be current marijuana users (AOR=7.1 [3.5–14.2]). Unexpectedly, household income and employment status were not associated with smoking status. Among current alcohol users, smokers consumed three times the number of drinks per month compared to nonsmokers (median 12 vs. 4, respectively; P<0.001). Among current marijuana users, smokers consumed over five times the number of joints per month compared to nonsmokers (median 22 vs. 4, respectively; P<0.001). Overall, lower education, divorce, alcohol and marijuana use were significantly associated with increased likelihood of smoking among this population.
doi:10.1080/14622200802238894
PMCID: PMC2896966  PMID: 18686179 CAMSID: cams1336
black African descent; smoking; socioeconomics; drug use

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