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1.  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.
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.
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.
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
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.
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.
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.
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
2.  Opioid antagonists for smoking cessation 
The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.
To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.
Search methods
We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies.
Selection criteria
We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence.
Data collection and analysis
We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model.
Main results
Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes.
Authors’ conclusions
Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.
PMCID: PMC4038652  PMID: 23744347
Buprenorphine [therapeutic use]; Naloxone [therapeutic use]; Naltrexone [therapeutic use]; Narcotic Antagonists [*therapeutic use]; Randomized Controlled Trials as Topic; Smoking [*drug therapy]; Smoking Cessation [*methods]; Tobacco Use Cessation Products; Humans
3.  Systematic review and meta-analysis of opioid antagonists for smoking cessation 
BMJ Open  2014;4(3):e004393.
This meta-analysis sought to evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. Post-treatment abstinence was examined as a secondary outcome and effects on withdrawal symptoms, craving and reduced consumption were also explored.
The search strategy for this meta-analysis included clinical trials (published and unpublished data) in the Cochrane Tobacco Addiction Group Specialized Register and MEDLINE.
Adult smokers.
We included randomised trials comparing opioid antagonists to placebo or an alternative therapy for smoking cessation and reported data on abstinence for a minimum of 6 months.
Primary and secondary outcome measures
Outcomes included smoking abstinence at long-term follow-up (primary); abstinence at end of treatment (secondary); and effects on withdrawal, craving and smoking consumption (exploratory).
8 trials with a total of 1213 participants were included. Half the trials examined the benefit of adding naltrexone versus placebo to nicotine replacement therapy (NRT). There was no significant difference between naltrexone and placebo alone (relative risk (RR) 1.00; 95% CI 0.66 to 1.51) or as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30), with an overall pooled estimate of RR 0.97; 95% CI 0.76 to 1.24. Findings for naltrexone effects on withdrawal, craving and reduced smoking were equivocal.
The findings indicate no beneficial effect of naltrexone alone or as an adjunct to NRT on short-term or long-term smoking abstinence. While further trials may narrow the confidence limits, they are unlikely to appreciably alter the conclusion.
PMCID: PMC3963070  PMID: 24633528
opioid antagonists ; smoking cessation; tobacco; smoking abstinence; naltrexone
4.  Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials 
We analyzed pooled data from two comparable randomized placebo-controlled clinical trials of bupropion pharmacotherapy for smoking cessation for which data on DRD2 Taq1A genotype were available. A total of 722 smokers across the two trials were randomized to 10 weeks of sustained-release bupropion hydrochloride or placebo. General estimating equation analysis demonstrated a significant gene × drug interaction (B=0.87, SE=0.34, p=.009). Smokers with the A2/A2 genotype using bupropion were more than three times as likely, relative to placebo, to be abstinent at end of treatment (35.2% vs. 15.1%; OR=3.25, 95% CI 2.00–5.28) and at 6 months of follow-up (26.7% vs. 12.2%; OR=2.81, 95% CI 1.66–4.77), which was attenuated by 12 months (16.3% vs. 10.7%; OR=1.70, 95% CI 0.95–3.05). We found no significant benefit of bupropion relative to placebo on smoking cessation outcomes at any time point in participants with A1/A1 or A1/A2 genotypes. These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype.
PMCID: PMC2128730  PMID: 18058343
5.  Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers 
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.
This study aims to investigate whether or not the relationship between smoking quantity and abdominal obesity is influenced by CYP2A6 genotypes.
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).
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.
Heavy smoking may increase the risk of abdominal obesity—particularly in smokers with CYP2A6 poor metabolizer genotypes.
PMCID: PMC4114962  PMID: 22160797
Cigarette smoking; CYP2A6 genotypes; Abdominal obesity; Interaction
6.  Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways 
To explore the interactions between smoking and CYP2A6 genotypes on type 2 diabetes (T2DM) as well as potential pathways for smoking in causing T2DM.
Cross-sectional study.
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.
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.
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.
PMCID: PMC4112659  PMID: 21964962
7.  Pharmacogenetics of Smoking Cessation in General Practice: Results From the Patch II and Patch in Practice Trials 
Nicotine & Tobacco Research  2011;13(3):157-167.
Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that ‘one size fits all’ smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice.
New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach.
By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed.
The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.
PMCID: PMC3107615  PMID: 21330274
8.  Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans 
Nicotine & Tobacco Research  2010;12(3):251-262.
The 11q23.1 genomic region has been associated with nicotine dependence in Black and White Americans.
By conducting linkage disequilibrium analyses of 7 informative single nucleotide polymorphisms (SNPs) within the tetratricopeptide repeat domain 12 (TTC12)/ankyrin repeat and kinase containing 1 (ANKK1)/dopamine (D2) receptor gene cluster, we identified haplotype block structures in 270 Black and 368 White (n = 638) participants, from the Baltimore Epidemiologic Catchment Area cohort study, spanning the TTC12 and ANKK1 genes consisting of three SNPs (rs2303380–rs4938015–rs11604671). Informative haplotypes were examined for sex-specific associations with daily tobacco smoking initiation and cessation using longitudinal data from 1993–1994 and 2004–2005 interviews.
There was a Haplotype × Sex interaction such that Black men possessing the GTG haplotype who were smokers in 1993–2004 were more likely to have stopped smoking by 2004–2005 (55.6% GTG vs. 22.0% other haplotypes), while Black women were less likely to have quit smoking if they possessed the GTG (20.8%) versus other haplotypes (24.0%; p = .028). In Whites, the GTG haplotype (vs. other haplotypes) was associated with lifetime history of daily smoking (smoking initiation; odds ratio = 1.6; 95% CI = 1.1–2.4; p = .013). Moreover, there was a Haplotype × Sex interaction such that there was higher prevalence of smoking initiation with GTG (77.6%) versus other haplotypes (57.0%; p = .043).
In 2 different ethnic American populations, we observed man–woman variation in the influence of the rs2303380–rs4938015–rs11604671 GTG haplotype on smoking initiation and cessation. These results should be replicated in larger cohorts to establish the relationship among the rs2303380–rs4938015–rs11604671 haplotype block, sex, and smoking behavior.
PMCID: PMC2825103  PMID: 20133381
9.  Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data 
Nicotine & Tobacco Research  2009;11(1):64-76.
Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence.
Our a priori hypothesis was that the association of the DRD2 Taq1A polymorphism with smoking behavior would be more prominent in females than males. We therefore investigated the strength of evidence for an association between the DRD2 Taq1A polymorphism and smoking behavior in a large sample of females and used meta-analytic techniques to synthesize existing published data and explore the role of sex in explaining any heterogeneity between studies.
We did not observe any strong evidence of association between the DRD2 Taq1A polymorphism and smoking behavior, including smoking initiation, smoking persistence, and smoking rate, either in our female sample or in our meta-analysis of 29 studies, comprising 28 published studies and the data from the present study. Metaregression suggested an association between the proportion of male participants in a study and the individual study effect size, indicating a larger effect size with a greater proportion of male participants for smoking initiation and smoking persistence. This effect did not appear to be due to the inclusion of the data from the present study.
Available evidence does not support an association between the DRD2 Taq1A polymorphism and smoking behavior. Contrary to our a priori hypothesis, we found evidence of a stronger association in males than in females.
PMCID: PMC3203402  PMID: 19246443
10.  Pharmacogenetic Smoking Cessation Intervention in a Health Care Setting: A Pilot Feasibility Study 
Nicotine & Tobacco Research  2012;15(2):518-526.
There is increasing evidence that response to pharmacological treatment for nicotine dependence may be moderated by genetic polymorphisms. However, the feasibility, acceptability, and impact of genetically tailoring treatment in real-world clinical settings are unknown.
We conducted a multiphased, mixed-methods feasibility study with current smokers to develop and evaluate a patient-centered, theoretically grounded personalized medicine treatment protocol. The initial research phase included formative work to develop intervention materials. The second phase included a randomized pilot trial to evaluate the intervention. Trial participants (n = 36) were genotyped for ANKK1 rs1800497 and were randomized to receive genetic feedback (GF) plus standard behavioral counseling (BC) for smoking cessation or BC without GF. All participants received genetically tailored pharmacotherapy (nicotine patch or bupropion).
The intervention was feasible to implement and was acceptable to participants based on satisfaction ratings and objective measures of participation. There was no evidence that the GF resulted in adverse psychological outcomes (e.g., depression, fatalism, reduced perceived control over quitting, differential motivation for quitting) based on quantitative or qualitative outcomes.
Study results suggest that it is feasible to offer treatment within a health care setting that includes genetically tailored pharmacotherapy and doing so had no apparent adverse psychological impacts. Further evaluation of pharmacogenetically tailored smoking cessation interventions appears warranted.
PMCID: PMC3611995  PMID: 22949583
11.  A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation 
We conducted a cost-effectiveness analysis of genetic testing for smoking cessation, based on data available from the published pharmacogenetic studies of nicotine replacement therapy and bupropion, and a previous cost-effectiveness analysis of smoking cessation treatments. We use multiparameter evidence synthesis methods to combine evidence on cessation by genotype with evidence on cessation irrespective of genotype (which can be written as a function of genotype-specific parameters). Our intention was to explore the most cost-effective approach to prescribing smoking cessation pharmacotherapy, given the hypothetical availability of a test based on a single-gene variant that has been reported to predict treatment response. We considered four types of treatment: nicotine replacement therapy (NRT) pharmacotherapy, bupropion SR pharmacotherapy, combination NRT and bupropion, and standard care as the control. Two scenarios were investigated, one in which the control represented brief advice and the other in which the control represented individual counseling. Strategies that either do not test for dopamine D2 receptor (DRD2) genotype (each individual receives the same treatment), or do test for DRD2 genotype (treatment allocated according to genotype), were evaluated. Our results indicated that the most cost-effective strategy in our hypothetical example of a single-gene test to aid prescription of smoking cessation pharmacotherapy is to prescribe both NRT and bupropion regardless of genotype, as a first-line treatment for smoking cessation. We conclude that it should not be assumed that genetic tailoring will necessarily be more cost-effective than applying the current “one-size-fits-all” model of pharmacotherapy for smoking cessation. In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest.
PMCID: PMC2257987  PMID: 18188764
12.  Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation 
This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N=291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3′ VNTR), and cytochrome P450 2B6 (CYP2B6 1459 C→T) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 × bupropion interaction (B=1.49, SE=0.59, p=.012) and a three-way DRD2 × bupropion × craving interaction on 6-month smoking cessation outcomes (B=−0.45, SE=0.22, p=.038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 × CYP2B6 interaction (B=1.43, SE=0.56, p=.01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene × gene and gene × craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.
PMCID: PMC2039873  PMID: 17654295
13.  The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: Follow-up of a randomized controlled trial 
In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotype×treatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care–based trial.
PMCID: PMC2031912  PMID: 17365753
15.  Chronic psychosocial stressors and salivary biomarkers in emerging adults 
Psychoneuroendocrinology  2011;37(8):1158-1170.
We investigated whole saliva as a source of biomarkers to distinguish individuals who have, and who have not, been chronically exposed to severe and threatening life difficulties. We evaluated RNA and DNA metrics, expression of 37 candidate genes, and cortisol release in response to the Trier Social Stress Test, as well as clinical characteristics, from 48 individuals stratified on chronic exposure to psychosocial stressors within the last year as measured by the Life Events and Difficulties Schedule. Candidate genes were selected based on their differential gene expression ratio in circulating monocytes from a published genome-wide analysis of adults experiencing different levels of exposure to a chronic stressor.
In univariate analyses, we observed significantly decreased RNA integrity (RIN) score (P = 0.04), and reduced expression of glucocorticoid receptor-regulated genes (Ps < 0.05) in whole saliva RNA from individuals exposed to chronic stressors, as compared to those with no exposure. In those exposed, we observed significantly decreased BMI (P < 0.001), increased ever-smoking and increased lifetime alcohol abuse or dependence (P ≤ 0.03), and a reduction of cortisol release. In post hoc multivariate analyses including clinical and biospecimen-derived variables, we consistently observed significantly decreased expression of IL8 (Ps < 0.05) in individuals exposed, with no significant association to RIN score. Alcohol use disorders, tobacco use, a reduced acute stress response and decreased salivary IL8 gene expression characterize emerging adults chronically exposed to severe and threatening psychosocial stressors.
PMCID: PMC3774595  PMID: 22172638
Human; Saliva; Gene expression; IL8; qPCR
16.  PharmGKB Summary - Very Important Pharmacogene Information for Cytochrome P-450, Family 2, Subfamily A, polypeptide 6 (CYP2A6) 
Pharmacogenetics and genomics  2012;22(9):695-708.
PMCID: PMC3413746  PMID: 22547082
CYP2A6; inter-individual variation; pharmacokinetics; genetic polymorphisms; drug metabolism; drug efficacy
17.  Potential Reporting Bias in fMRI Studies of the Brain 
PLoS ONE  2013;8(7):e70104.
Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants.
After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher’s z transformation.
Principal Findings
There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies.
These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.
PMCID: PMC3723634  PMID: 23936149
18.  The neuroeconomics of nicotine dependence: A preliminary study of delay discounting of monetary and cigarette rewards in smokers using fMRI 
Psychiatry research  2012;202(1):20-29.
Neuroeconomics integrates behavioral economics and cognitive neuroscience to understand the neurobiological basis for normative and maladaptive decision making. Delay discounting is a behavioral economic index of impulsivity that reflects capacity to delay gratification and has been consistently associated with nicotine dependence. This preliminary study used functional magnetic resonance imaging to examine delay discounting for money and cigarette rewards in 13 nicotine dependent adults. Significant differences between preferences for smaller immediate rewards and larger delayed rewards were evident in a number of regions of interest (ROIs), including the medial prefrontal cortex, anterior insular cortex, middle temporal gyrus, middle frontal gyrus, and cingulate gyrus. Significant differences between money and cigarette rewards were generally lateralized, with cigarette choices associated with left hemisphere activation and money choices associated with right hemisphere activation. Specific ROI differences included the posterior parietal cortex, medial and middle frontal gyrus, ventral striatum, temporoparietal cortex, and angular gyrus. Impulsivity as measured by behavioral choices was significantly associated with both individual ROIs and a combined ROI model. These findings provide initial evidence in support of applying a neuroeconomic approach to understanding nicotine dependence.
PMCID: PMC3530421  PMID: 22633679
Nicotine dependence; smoking; tobacco; behavioral economics; neuroeconomics; delay discounting; impulsivity
19.  Smoking and Genetic Risk Variation across Populations of European, Asian, and African-American Ancestry - A Meta-analysis of Chromosome 15q25 
Genetic epidemiology  2012;36(4):340-351.
Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations.
Association results for a dichotomized cigarettes smoked per day (CPD) phenotype in 27 datasets (European ancestry (N=14,786), Asian (N=6,889), and African American (N=10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations.
We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (p < 0.01) in each of these three populations (OR=1.33, 95%C.I.=1.25–1.42, p=1.1×10−17 in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans.
The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.
PMCID: PMC3387741  PMID: 22539395
smoking; genetics; meta-analysis; cross-population
20.  Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women 
Drug and alcohol dependence  2011;120(1-3):7-13.
Tobacco smoking is the leading preventable cause of death in the developed world. Identifying risk factors for smoking may lead to more effective treatments. Genome wide association studies revealed a relationship between development of nicotine dependence and a single-nucleotide polymorphism (SNP, rs16969968) of the nicotine acetylcholine receptor (nAChR) alpha-5 subunit gene (CHRNA5). The relationship between this SNP and other factors contributing to smoking behavior such as smoking cue reactivity is unclear.
We assessed the role of rs16969968 on brain functional MRI (fMRI) reactivity to smoking cues by studying nicotine dependent women with the nicotine dependence ‘risk’ allele (A allele, N=14) and without the ‘risk’ allele (G/G smokers, N=10). Nicotine dependence severity, as assessed with the Fagerstrom test for nicotine dependence, smoking pack-years, and expired carbon monoxide levels, were equivalent in these groups.
We observed a group difference in fMRI reactivity; women without the A allele (G/G smokers) showed greater fMRI reactivity to smoking images in brain areas related to memory and habitual behavior such as the hippocampus and dorsal striatum.
Our finding suggests that nicotine-dependent smokers lacking the rs16969968 A allele are more likely to recall smoking-related memories and engage in habitual responding to smoking cues than A allele smokers. Although more studies are necessary to determine the mechanism underlying and significance of this cue reactivity difference, these data suggest that smokers may develop and remain nicotine dependent due to different factors including genetics and cue reactivity. This finding may have implications for personalizing smoking treatment.
PMCID: PMC3203995  PMID: 21764527
Tobacco smoking; fMRI; CHRNA5; nicotine dependence; dorsal striatum
21.  Dopamine D4 Receptor Gene Variation Moderates the Efficacy of Bupropion for Smoking Cessation 
The Pharmacogenomics Journal  2010;12(1):86-92.
Smokers (≥10 cig/day; N =331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion plus counseling for smoking cessation were genotyped for a VNTR polymorphism in Exon-III of the Dopamine D4 receptor (DRD4) gene. Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2, 6, and 12-months post-end of treatment indicated that bupropion (vs. placebo) predicted increased odds of abstinence. The main effect of Genotype was not significant. A Genotype × Treatment interaction (p=.005) showed that bupropion predicted increased odds of abstinence in long-allele carriers (OR=1.31, p<.0001), whereas bupropion was not associated with abstinence among short-allele homozygotes (OR=1.06, p=.23). The Genotype × Treatment interaction remained when controlling for demographic and clinical covariates (p=.01) and in analyses predicting continuous abstinence (ps≤.054). Bupropion may be more efficacious for smokers who carry the long-allele, which is relevant to personalized pharmacogenetic treatment approaches.
PMCID: PMC2981689  PMID: 20661272
DRD4; VNTR; smoking cessation; bupropion; pharmacogenetic
22.  Associations of CYP2A6 genotype with smoking behaviors in southern China 
Addiction (Abingdon, England)  2011;106(5):985-994.
To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers.
Case-only genetic association study.
Southern China
A total of 1,328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007.
All participants were answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6 *4, *5, *7, *9 and *10) were genotyped.
The frequencies of CYP2A6 *4, *5, *7, *9 and *10 alleles were 8.5%, 1.2%, 6.3%, 13.5% and 2.4%, which corresponded to 48.9%, 15.4%, 24.2% and 11.5% of participants being classified as normal, intermediate, slow and poor metabolizers, respectively. Multivariate analyses demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day (adjusted OR = 0.49; 95% CI: 0.32–0.76), started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06–2.26) and, amongst former smokers, reported smoking for a shorter duration prior to quitting (adjusted OR = 0.33; 95% CI: 0.12–0.94). However, poor metabolizers were less likely to quit smoking and remain abstinent than normal metabolizers (OR = 0.54; 95% CI: 0.34–0.86).
Reduced metabolism function of CYP2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.
PMCID: PMC3074015  PMID: 21205058
CYP2A6; genetic polymorphisms; smoking behavior; Chinese smokers
23.  Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence 
PLoS Genetics  2011;7(9):e1002280.
Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (<1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.
Author Summary
An individual's genetic profile plays an important role in determining risk for disease and response to medical therapy. The development of technologies that facilitate rapid whole-genome sequencing will provide unprecedented power in the estimation of disease risk. Here we develop methods to characterize genetic determinants of disease risk and response to medical therapy in a nuclear family of four, leveraging population genetic profiles from recent large scale sequencing projects. We identify the way in which genetic information flows through the family to identify sequencing errors and inheritance patterns of genes contributing to disease risk. In doing so we identify genetic risk factors associated with an inherited predisposition to blood clot formation and response to blood thinning medications. We find that this aligns precisely with the most significant disease to occur to date in the family, namely pulmonary embolism, a blood clot in the lung. These ethnicity-specific, family-based approaches to interpretation of individual genetic profiles are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.
PMCID: PMC3174201  PMID: 21935354
25.  Smoking cessation in primary care 
BMJ : British Medical Journal  2008;336(7655):1200-1201.
Evidence does not support routine use of combination therapy with nortriptyline
PMCID: PMC2405833  PMID: 18441374

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