Sean P. David, M.D., D.Phil.

Journal Articles

Biomarkers for smoking cessation. Clinical pharmacology & therapeutics Bough, K. J., Lerman, C., Rose, J. E., McClernon, F. J., Kenny, P. J., Tyndale, R. F., David, S. P., Stein, E. A., Uhl, G. R., Conti, D. V., Green, C., Amur, S. 2013; 93 (6): 526-538
Abstract

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.

View details for DOI 10.1038/clpt.2013.57

View details for PubMedID 23588313
Pharmacogenetic Smoking Cessation Intervention in a Health Care Setting: A Pilot Feasibility Study NICOTINE & TOBACCO RESEARCH McClure, J. B., Swan, G. E., St John, J., Fauver, R., Javitz, H. S., Bergen, A. W., Nishita, D., Niaura, R., Munafo, M. R., David, S. P. 2013; 15 (2): 518-526
Abstract

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.

View details for DOI 10.1093/ntr/nts173

View details for Web of Science ID 000313826600027

View details for PubMedID 22949583
Potential reporting bias in FMRI studies of the brain. PloS one David, S. P., Ware, J. J., Chu, I. M., Loftus, P. D., Fusar-Poli, P., Radua, J., Munafò, M. R., Ioannidis, J. P. 2013; 8 (7)
Abstract

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.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.

View details for DOI 10.1371/journal.pone.0070104

View details for PubMedID 23936149
Tobacco dependence treatment teaching by medical school clerkship preceptors: Survey responses from more than 1000 US medical students. Preventive medicine Geller, A. C., Hayes, R. B., Leone, F., Churchill, L. C., Leung, K., Reed, G., Jolicoeur, D., Okuliar, C., Adams, M., Murray, D. M., Liu, Q., Waugh, J., David, S., Ockene, J. K. 2013
Abstract

OBJECTIVE: To determine factors associated with tobacco cessation counseling in medical school clerkships. METHODS: Third-year medical students at 10 medical schools across the United States completed a 100-item survey, measuring the frequency with which they experienced their preceptors providing clinical teaching components: clear instruction, feedback, modeling behavior, setting clear objectives, and responding to questions about tobacco dependence counseling as well as frequency of use of tobacco prompts and office systems. Our primary dependent measure was student self-reported skill level for items of tobacco dependence treatment (e.g. "5As"). RESULTS: Surveys were completed by 1213 students. For both family medicine and internal medicine clerkships, modeling and providing clear instruction on ways to provide tobacco counseling were reported most commonly. In contrast, providing feedback and clear objectives for tobacco dependence treatment lagged behind. Overall, students who reported preceptors' provision of optimal clinical teaching components and office system prompts in both family medicine and internal medicine clerkships had higher self-reported skill (P<0.001) than students with no exposure or exposure during only one of the clerkships. CONCLUSIONS: Future educational interventions intended to help students adopt effective tobacco dependence treatment techniques should be engineered to facilitate these critical precepting components.

View details for PubMedID 23623894
Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion Addiction David, S. P., Strong, D. R., Leventhal, A. M., Lancaster, M. A., McGeary, J. E., Munafò, M. R., Bergen, A. W., Swan, G. E., Benowitz, N. L., Tyndale, R. F., Conti, D. V., Brown, R. A., Lerman, C., Niaura, R. 2013; 108 (12): 2202-11
View details for DOI 10.1111/add.12325
Opioid antagonists for smoking cessation COCHRANE DATABASE OF SYSTEMATIC REVIEWS David, S. P., Lancaster, T., Stead, L. F., Evins, A. E., Prochaska, J. J. 2013
Abstract

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.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.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.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.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.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.

View details for DOI 10.1002/14651858.CD003086.pub3

View details for Web of Science ID 000321124000022

View details for PubMedID 23744347
Evidence of reporting biases in voxel-based morphometry (VBM) studies of psychiatric and neurological disorders. Human Brain Mapping Fusar-Poli, P., Joaquim, R., Marianna, F., Andrea, M., Stefan, B., Fabio, D., Massimo, B., Ioannidis, J. P., David, S. P. 2013
View details for DOI 10.1002/hbm.22384
PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6 PHARMACOGENETICS AND GENOMICS McDonagh, E. M., Wassenaar, C., David, S. P., Tyndale, R. F., Altman, R. B., Whirl-Carrillo, M., Klein, T. E. 2012; 22 (9): 695-708
View details for DOI 10.1097/FPC.0b013e3283540217

View details for Web of Science ID 000307652600006

View details for PubMedID 22547082
Smoking and Genetic Risk Variation Across Populations of European, Asian, and African American Ancestry-A Meta-Analysis of Chromosome 15q25 GENETIC EPIDEMIOLOGY Chen, L., Saccone, N. L., Culverhouse, R. C., Bracci, P. M., Chen, C., Dueker, N., Han, Y., Huang, H., Jin, G., Kohno, T., Ma, J. Z., Przybeck, T. R., Sanders, A. R., Smith, J. A., Sung, Y. J., Wenzlaff, A. S., Wu, C., Yoon, D., Chen, Y., Cheng, Y., Cho, Y. S., David, S. P., Duan, J., Eaton, C. B., Furberg, H., Goate, A. M., Gu, D., Hansen, H. M., Hartz, S., Hu, Z., Kim, Y. J., Kittner, S. J., Levinson, D. F., Mosley, T. H., Payne, T. J., Rao, D. C., Rice, J. P., Rice, T. K., Schwantes-An, T., Shete, S. S., Shi, J., Spitz, M. R., Sun, Y. V., Tsai, F., Wang, J. C., Wrensch, M. R., Xian, H., Gejman, P. V., He, J., Hunt, S. C., Kardia, S. L., Li, M. D., Lin, D., Mitchell, B. D., Park, T., Schwartz, A. G., Shen, H., Wiencke, J. K., Wu, J., Yokota, J., Amos, C. I., Bierut, L. J. 2012; 36 (4): 340-351
Abstract

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 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 (odds ratio [OR] = 1.33, 95% CI = 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.

View details for DOI 10.1002/gepi.21627

View details for Web of Science ID 000303319900006

View details for PubMedID 22539395
Genome-wide meta-analyses of smoking behaviors in African Americans TRANSLATIONAL PSYCHIATRY David, S. P., Hamidovic, A., Chen, G. K., Bergen, A. W., Wessel, J., Kasberger, J. L., BROWN, W. M., Petruzella, S., Thacker, E. L., Kim, Y., Nalls, M. A., Tranah, G. J., Sung, Y. J., Ambrosone, C. B., Arnett, D., Bandera, E. V., Becker, D. M., BECKER, L., Berndt, S. I., Bernstein, L., Blot, W. J., Broeckel, U., Buxbaum, S. G., Caporaso, N., Casey, G., Chanock, S. J., Deming, S. L., Diver, W. R., Eaton, C. B., Evans, D. S., Evans, M. K., Fornage, M., Franceschini, N., Harris, T. B., Henderson, B. E., Hernandez, D. G., Hitsman, B., Hu, J. J., Hunt, S. C., Ingles, S. A., John, E. M., Kittles, R., Kolb, S., Kolonel, L. N., Le Marchand, L., Liu, Y., Lohman, K. K., McKnight, B., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M., Psaty, B. M., Rao, D. C., Redline, S., Rodriguez-Gil, J. L., Rybicki, B. A., Signorello, L. B., Singleton, A. B., Smoller, J., Snively, B., Spring, B., Stanford, J. L., Strom, S. S., Swan, G. E., Taylor, K. D., Thun, M. J., Wilson, A. F., Witte, J. S., Yamamura, Y., Yanek, L. R., Yu, K., Zheng, W., Ziegler, R. G., Zonderman, A. B., Jorgenson, E., Haiman, C. A., Furberg, H. 2012; 2
Abstract

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (? = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

View details for DOI 10.1038/tp.2012.41

View details for Web of Science ID 000312895700012

View details for PubMedID 22832964
The neuroeconomics of nicotine dependence: A preliminary functional magnetic resonance imaging study of delay discounting of monetary and cigarette rewards in smokers PSYCHIATRY RESEARCH-NEUROIMAGING MacKillop, J., Amlung, M. T., Wier, L. M., David, S. P., Ray, L. A., Bickel, W. K., Sweet, L. H. 2012; 202 (1): 20-29
Abstract

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.

View details for DOI 10.1016/j.pscychresns.2011.10.003

View details for Web of Science ID 000306622400003

View details for PubMedID 22633679
Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers ANNALS OF BEHAVIORAL MEDICINE Liu, T., David, S. P., Tyndale, R. F., Wang, H., Yu, X., Chen, W., Zhou, Q., Chen, W. 2012; 43 (2): 253-261
Abstract

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.

View details for DOI 10.1007/s12160-011-9318-5

View details for Web of Science ID 000301460500015

View details for PubMedID 22160797
Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence PLOS GENETICS Dewey, F. E., Chen, R., Cordero, S. P., Ormond, K. E., Caleshu, C., Karczewski, K. J., Whirl-Carrillo, M., Wheeler, M. T., Dudley, J. T., Byrnes, J. K., Cornejo, O. E., Knowles, J. W., Woon, M., Sangkuhl, K., Gong, L., Thorn, C. F., Hebert, J. M., Capriotti, E., David, S. P., Pavlovic, A., West, A., Thakuria, J. V., Ball, M. P., Zaranek, A. W., Rehm, H. L., Church, G. M., West, J. S., Bustamante, C. D., Snyder, M., Altman, R. B., Klein, T. E., Butte, A. J., Ashley, E. A. 2011; 7 (9)
Abstract

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.

View details for DOI 10.1371/journal.pgen.1002280

View details for Web of Science ID 000295419100031

View details for PubMedID 21935354
Associations of CYP2A6 genotype with smoking behaviors in southern China ADDICTION Liu, T., David, S. P., Tyndale, R. F., Wang, H., Zhou, Q., Ding, P., He, Y., Yu, X., Chen, W., Crump, C., Wen, X., Chen, W. 2011; 106 (5): 985-994
Abstract

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 1328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007.All participants answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles were genotyped for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6*4,*5,*7,*9 and *10).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 in male smokers demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day [adjusted odds ratio (OR) = 0.49; 95% confidence interval (CI): 0.32-0.76], started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06-2.26) and, among 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 (adjusted OR = 0.54; 95% CI: 0.34-0.86). Conclusions: Reduced metabolism function of cytochrome P450 2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.

View details for DOI 10.1111/j.1360-0443.2010.03353.x

View details for Web of Science ID 000289296900035

View details for PubMedID 21205058
Genome-wide association for smoking cessation success: participants in the Patch in Practice trial of nicotine replacement PHARMACOGENOMICS Uhl, G. R., Drgon, T., Johnson, C., Walther, D., Aveyard, P., Murphy, M., Johnstone, E. C., Munafo, M. R. 2010; 11 (3): 357-367
Abstract

To confirm and extend to primary care settings prior genome-wide association results that distinguish smokers who successfully quit from individuals who were not able to quit smoking in clinical trials.Affymetrix 6.0 Arrays were used to study DNA from successful quitters and matched individuals who did not quit from the Patch in Practice study of 925 smokers in 26 UK general practices who were provided with 15 mg/16 h nicotine-replacement therapy and varying degrees of behavioral support.Only a few SNPs provided results near 'genome-wide' levels of significance. Nominally significant (p < 0.01) SNP results identify the same chromosomal regions identified by prior genome-wide association studies to a much greater extent than expected by chance.Ability to change smoking behavior in a general practice setting appears to share substantial underlying genetics with the ability to change this behavior in clinical trials, though the modest sample sizes available for these studies provides some caution to these conclusions.

View details for DOI 10.2217/PGS.09.156

View details for Web of Science ID 000276291100016

View details for PubMedID 20235792
Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans NICOTINE & TOBACCO RESEARCH David, S. P., Mezuk, B., Zandi, P. P., Strong, D., Anthony, J. C., Niaura, R., Uhl, G. R., Eaton, W. W. 2010; 12 (3): 251-262
Abstract

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 x 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 x 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.

View details for DOI 10.1093/ntr/ntp201

View details for Web of Science ID 000274778400009

View details for PubMedID 20133381
Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: New data from the Patch in Practice trial and pooled analyses DRUG AND ALCOHOL DEPENDENCE David, S. P., Johnstone, E. C., Murphy, M. F., Aveyardd, P., Guo, B., Lerman, C., Munafo, M. R. 2008; 98 (1-2): 77-85
Abstract

The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A45-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p=0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p=0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p=0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p=0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p=0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p=0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N=1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR)=1.25, 95% CI 0.89, 1.74, p=0.19; SS: OR=1.31, 95% CI 0.86, 1.98, p=0.21) or 26-week follow-up (Reference LL; SL: OR=0.93, 95% CI 0.64, 1.33, p=0.68; SS: OR=1.00, 95% CI 0.63, 1.58, p=1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.

View details for DOI 10.1016/j.drugalcdep.2008.04.013

View details for Web of Science ID 000259768500010

View details for PubMedID 18562131
Genetic variation in the dopamine pathway and smoking cessation PHARMACOGENOMICS David, S. P., Munafo, M. R. 2008; 9 (9): 1307-1321
Abstract

Twin and family studies have established that genetic factors account for much of the variation in tobacco dependence. Therefore, identification of genetic variants predictive of successful smoking cessation has implications for the future prospect of personalized smoking cessation therapies. Converging data implicate the dopamine pathway as an important neural substrate for tobacco dependence. Several candidate genes within the dopamine pathway (e.g., DRD2 and COMT) have been reported to be associated with the efficacy of bupropion and nicotine replacement therapy, and others (e.g., SLC6A3 and DRD4) have been reported to be associated with smoking cessation independent of pharmacotherapy. However, few of these candidate genes are present within regions of suggestive or significant linkage or overlap with genome-wide linkage or association studies of tobacco dependence or smoking cessation. Future studies should seek to replicate genome-wide association analyses with individual-level genotyping, and use better-defined smoking cessation phenotypes. Once robust evidence for association is established, which may take several more years, further research into the likely cost-effectiveness, feasibility and acceptability of personalized medicine for smoking cessation will be necessary before it can be translated into practice.

View details for DOI 10.2217/14622416.9.9.1307

View details for Web of Science ID 000259533200017

View details for PubMedID 18781857
Molecular genetics of successful smoking cessation - Convergent genome-wide association study results ARCHIVES OF GENERAL PSYCHIATRY Uhl, G. R., Liu, Q., Drgon, T., Johnson, C., Walther, D., David, S. P., Niaura, R., Lerman, C., Rose, E. 2008; 65 (6): 683-693
Abstract

Smoking remains a major public health problem. Twin studies indicate that the ability to quit smoking is substantially heritable, with genetics that overlap modestly with the genetics of vulnerability to dependence on addictive substances.To identify replicated genes that facilitate smokers' abilities to achieve and sustain abstinence from smoking (herein after referred to as quit-success genes) found in more than 2 genome-wide association (GWA) studies of successful vs unsuccessful abstainers, and, secondarily, to nominate genes for selective involvement in smoking cessation success with bupropion hydrochloride vs nicotine replacement therapy (NRT).The GWA results in subjects from 3 centers, with secondary analyses of NRT vs bupropion responders.Outpatient smoking cessation trial participants from 3 centers.European American smokers who successfully vs unsuccessfully abstain from smoking with biochemical confirmation in a smoking cessation trial using NRT, bupropion, or placebo (N = 550).Quit-success genes, reproducibly identified by clustered nominally positive single-nucleotide polymorphisms (SNPs) in more than 2 independent samples with significant P values based on Monte Carlo simulation trials. The NRT-selective genes were nominated by clustered SNPs that display much larger t values for NRT vs placebo comparisons. The bupropion-selective genes were nominated by bupropion-selective results.Variants in quit-success genes are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, and/or protein-handling functions. Quit-success genes are identified by clustered nominally positive SNPs from more than 2 samples and are unlikely to represent chance observations (Monte Carlo P< .0003). These genes display modest overlap with genes identified in GWA studies of dependence on addictive substances and memory.These results support polygenic genetics for success in abstaining from smoking, overlap with genetics of substance dependence and memory, and nominate gene variants for selective influences on therapeutic responses to bupropion vs NRT. Molecular genetics should help match the types and/or intensity of antismoking treatments with the smokers most likely to benefit from them.

View details for Web of Science ID 000256403600009

View details for PubMedID 18519826
Smoking cessation in primary care BRITISH MEDICAL JOURNAL David, S. P., Munafo, M. R. 2008; 336 (7655): 1200-1201
View details for DOI 10.1136/bmj.39546.520694.80

View details for Web of Science ID 000256612700002

View details for PubMedID 18441374
Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch PHARMACOGENOMICS JOURNAL David, S. P., Munafo, M. R., Murphy, M. F., Proctor, M., Walton, R. T., Johnstone, E. C. 2008; 8 (2): 122-128
Abstract

Smokers of European ancestry (n=720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position -521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P=0.001) and 26-week (P=0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P=0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.

View details for DOI 10.1038/sj.tpj.6500447

View details for Web of Science ID 000254123900006

View details for PubMedID 17387332
Smoking cessation. BMJ (Clinical research ed.) Koplan, K. E., David, S. P., Rigotti, N. A. 2008; 336 (7637): 217-?
View details for DOI 10.1136/bmj.39248.531748.47

View details for PubMedID 18219045
Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion. Addiction David, S. P., Strong, D. R., Leventhal, A. M., Lancaster, M. A., McGeary, J. E., Munafò, M. R., Bergen, A. W., Swan, G. E., Benowitz, N. L., Tyndale, R. F., Conti, D. V., Brown, R. A., Lerman, C., Niaura, R. 2013; 108 (12): 2202-2211
Abstract

To evaluate the 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 into 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).A total of 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 [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) 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 standard error = -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.

View details for DOI 10.1111/add.12325

View details for PubMedID 23941313
Communities of Solution: Partnerships for Population Health JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE Griswold, K. S., Lesko, S. E., Westfall, J. M. 2013; 26 (3): 232-238
Abstract

Communities of solution (COSs) are the key principle for improving population health. The 1967 Folsom Report explains that the COS concept arose from the recognition that complex political and administrative structures often hinder problem solving by creating barriers to communication and compromise. A 2012 reexamination of the Folsom Report resurrects the idea of the COS and presents 13 grand challenges that define the critical links among community, public health, and primary care and call for ongoing demonstrations of COSs grounded in patient-centered care. In this issue, examples of COSs from around the country demonstrate core principles and propose visions of the future. Essential themes of each COS are the crossing of "jurisdictional boundaries," community-led or -oriented initiatives, measurement of outcomes, and creating durable connections with public health.

View details for DOI 10.3122/jabfm.2013.03.130102

View details for Web of Science ID 000318768600002

View details for PubMedID 23657688
Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers JOURNAL OF HUMAN HYPERTENSION Liu, T., Tyndale, R. F., David, S. P., Wang, H., Yu, X., Chen, W., Wen, X., Chen, W. 2013; 27 (1): 24-30
Abstract

The purpose of this study was to assess whether cytochrome P450 enzyme 2A6 (CYP2A6) genotypes moderate the association between smoking and hypertension. In this study, 954 Chinese male current smokers from a community-based chronic disease screening project in Guangzhou were interviewed with a structured questionnaire about socio-demographic status, smoking and other health-related behaviors. Blood was collected for DNA extraction and CYP2A6 genotyping. Hypertension was defined according to 2007 ESH-ESC Practice Guidelines. A multivariate logistic regression was performed to examine the interaction between smoking quantity and CYP2A6 genotypes on hypertension after adjusting for age, education level and other potential confounders. Multivariate analyses indicated that smoking more than 15 cigarettes per day significantly increased the risk of hypertension (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.21-2.10) compared with smoking 1-15 cigarettes per day, and further suggested that smoking interacted with normal CYP2A6 metabolizer genotype to increase the risk of hypertension. Smokers consuming more than 15 cigarettes per day with normal CYP2A6 metabolizer genotypes had the highest risk of hypertension (OR=2.04, 95% CI=1.11-3.75) compared with those consuming 1-15 cigarettes per day with slower CYP2A6 metabolizer genotypes. These findings demonstrated that smoking quantity was positively associated with hypertension and that CYP2A6 genotypes may moderate this relationship.

View details for DOI 10.1038/jhh.2011.111

View details for Web of Science ID 000311994000005

View details for PubMedID 22217675
No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women. Menopause (New York, N.Y.) Passarelli, M. N., Newcomb, P. A., Makar, K. W., Burnett-Hartman, A. N., Phipps, A. I., David, S. P., Hsu, L., Harrison, T. A., Hutter, C. M., Duggan, D. J., White, E., Chan, A. T., Peters, U. 2013
Abstract

Sex steroid hormones play a role in colorectal cancer (CRC) development, but little is known about their influence on tumor progression and metastasis. Because catechol-O-methyltransferase (COMT; 22q11.21) activity is an important component of estrogen-mediated carcinogenesis, we hypothesized that germline variation in COMT may be associated with CRC survival.We identified 10 single nucleotide polymorphisms that tagged variation across two isoforms of COMT in 2,458 women with CRC from the Nurses' Health Study, Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry, VITamins And Lifestyle Study, and Women's Health Initiative. All four studies participated in the Genetics and Epidemiology of Colorectal Cancer Consortium.During a median follow-up of 7 years across all studies, there were 799 deaths, including 566 deaths from CRC. Based on multiple comparisons, no associations between single nucleotide polymorphisms and CRC-specific or overall survival reached statistical significance, including the well-characterized Val108/158Met polymorphism (rs4680; CRC-specific survival: hazard ratio per minor allele, 1.04; 95% CI, 0.92-1.17; overall survival: hazard ratio per minor allele, 1.01; 95% CI, 0.90-1.14).In this large study of women with CRC, we find no evidence that common inherited variation in COMT is associated with survival time after diagnosis.

View details for PubMedID 23880798
Improving America's health requires community-level solutions: Folsom revisited. American family physician 2012; 86 (4): 1-2
Abstract

Amidst sweeping changes to health care in the 1960s, the broadly influential Folsom Commission report, "Health is a Community Affair," never fully achieved its vision of galvanizing the creation of Communities of Solution, which were empowered to improve health at the local level. Passage of health care reform, and persistent concern over poor health outcomes despite runaway spending, contemporizes Folsom's call for nationally supported and evaluated, but community-driven, solutions to the nation's health care challenges.

View details for PubMedID 23130357
Chronic psychosocial stressors and salivary biomarkers in emerging adults PSYCHONEUROENDOCRINOLOGY Bergen, A. W., Mallick, A., Nishita, D., Wei, X., Michel, M., Wacholder, A., David, S. P., Swan, G. E., Reid, M. W., Simons, A., Andrews, J. A. 2012; 37 (8): 1158-1170
Abstract

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.

View details for DOI 10.1016/j.psyneuen.2011.11.010

View details for Web of Science ID 000306583100003

View details for PubMedID 22172638
Communities of Solution: The Folsom Report Revisited ANNALS OF FAMILY MEDICINE Lesko, S., Griswold, K. S., David, S. P., Bazemore, A. W., Duane, M., Morgan, T., Westfall, J. M., Koop, C. E., Garrett, B., Puffer, J. C., Green, L. A. 2012; 10 (3): 250-260
Abstract

Efforts to address the current fragmented US health care structure, including controversial federal reform, cannot succeed without a reinvigoration of community-centered health systems. A blueprint for systematic implementation of community services exists in the 1967 Folsom Report--calling for "communities of solution." We propose an updated vision of the Folsom Report for integrated and effective services, incorporating the principles of community-oriented primary care. The 21st century primary care physician must be a true public health professional, forming partnerships and assisting data sharing with community organizations to facilitate healthy changes. Current policy reform efforts should build upon Folsom Report's goal of transforming personal and population health.

View details for DOI 10.1370/afm.1350

View details for Web of Science ID 000304723700011

View details for PubMedID 22585890
Dopamine D4 receptor gene variation moderates the efficacy of bupropion for smoking cessation PHARMACOGENOMICS JOURNAL Leventhal, A. M., David, S. P., Brightman, M., Strong, D., McGeary, J. E., Brown, R. A., Lloyd-Richardson, E. E., Munafo, M., Uhl, G. R., Niaura, R. 2012; 12 (1): 86-92
Abstract

Smokers (?10 cigarettes per day, N=331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion along with counseling for smoking cessation were genotyped for a variable number of tandem repeats polymorphism in exon III of the dopamine D4 receptor gene. Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2, 6 and 12 months after the 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=0.005) showed that bupropion predicted increased odds of abstinence in long-allele carriers (odds ratios (OR)=1.31, P<0.0001), whereas bupropion was not associated with abstinence among short-allele homozygotes (OR=1.06, P=0.23). The Genotype × Treatment interaction remained when controlling for demographic and clinical covariates (P=0.01) and in analyses predicting continuous abstinence (P's?0.054). Bupropion may be more efficacious for smokers who carry the long allele, which is relevant to personalized pharmacogenetic treatment approaches.

View details for DOI 10.1038/tpj.2010.64

View details for Web of Science ID 000299719200010

View details for PubMedID 20661272
Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women DRUG AND ALCOHOL DEPENDENCE Janes, A. C., Smoller, J. W., David, S. P., Frederick, B. d., Haddad, S., Basu, A., Fava, M., Evins, A. E., Kaufman, M. J. 2012; 120 (1-3): 7-13
Abstract

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.

View details for DOI 10.1016/j.drugalcdep.2011.06.009

View details for Web of Science ID 000299499800002

View details for PubMedID 21764527
Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways EUROPEAN JOURNAL OF ENDOCRINOLOGY Liu, T., Chen, W., David, S. P., Tyndale, R. F., Wang, H., Chen, Y., Yu, X., Chen, W., Zhou, Q., Ling, W. 2011; 165 (6): 961-967
Abstract

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.

View details for DOI 10.1530/EJE-11-0596

View details for Web of Science ID 000297687900015

View details for PubMedID 21964962
Pharmacogenetics of Smoking Cessation in General Practice: Results From the Patch II and Patch in Practice Trials NICOTINE & TOBACCO RESEARCH David, S. P., Johnstone, E. C., Churchman, M., Aveyard, P., Murphy, M. F., Munafo, M. R. 2011; 13 (3): 157-?
Abstract

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.

View details for DOI 10.1093/ntr/ntq246

View details for Web of Science ID 000287747600001

View details for PubMedID 21330274
Effects of nicotine withdrawal on verbal working memory and associated brain response PSYCHIATRY RESEARCH-NEUROIMAGING Sweet, L. H., Mulligan, R. C., Finnerty, C. E., Jerskey, B. A., David, S. P., Cohen, R. A., Niaura, R. S. 2010; 183 (1): 69-74
Abstract

Previous literature has reported effects of nicotine withdrawal on brain function during cognitive tasks such as verbal working memory (VWM). Mechanisms of these withdrawal effects have not been clearly identified. Functional neuroimaging offers an objective method to examine brain mechanisms associated with observable behavior and subjective reports. To investigate these mechanisms, 12 smokers were administered a 2-Back VWM challenge during two functional magnetic resonance imaging sessions. Participants abstained from smoking prior to both sessions; however, they applied a nicotine patch before one session and a placebo patch prior to the other. Among regions that exhibited a significant response to the 2-Back during either session, withdrawal was associated with significantly greater deactivation in left and right temporal poles and left medial frontal gyrus. The magnitude of task-related activation showed a significant inverse relationship to craving in the majority of regions during placebo administration. Also, individual brain responses varied more during placebo, suggesting inefficient neural processing. Results suggest that differences in brain response to a VWM challenge during abstinence may be attributed to increased craving. Further deactivation of regions associated with the default network (medial frontal and anterior temporal clusters) during the placebo condition suggests further suspension of default activity, possibly to compensate for inefficient neural processing.

View details for DOI 10.1016/j.pscychresns.2010.04.014

View details for Web of Science ID 000280033600008

View details for PubMedID 20570495
Application of Functional Neuroimaging Methods to Nicotine Dependence. In: Brain Imaging in Behavioral Medicine and Neuropsychology. Edited by Cohen R. Springer, New York, NY, USA. (text book in press). David SP., Sweet L, Cohen R, MacKillop J, Mulligan RC, Niaura R. 2010
Dopamine Transporters: Chemistry, Biology, and Pharmacology. Clin Pharmacol Ther. David SP. 2009; 85 (1): 16-17.
Lifestyle Medicine by Gary Egger, Andrew Binns, and Stephen Rossner. Am J Lifestyle Med. David SP. 2009; 3 (9): 409.
Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data NICOTINE & TOBACCO RESEARCH Munafo, M. R., Timpson, N. J., David, S. P., Ebrahim, S., Lawlor, D. A. 2009; 11 (1): 64-76
Abstract

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.

View details for DOI 10.1093/ntr/ntn012

View details for Web of Science ID 000264188900009

View details for PubMedID 19246443
[Smoking cessation]. Praxis Koplan, K. E., David, S. P., Rigotti, N. A. 2008; 97 (22): 1185-1186
View details for DOI 10.1024/1661-8157.97.22.1185

View details for PubMedID 18979437
A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation NICOTINE & TOBACCO RESEARCH Welton, N. J., Johnstone, E. C., David, S. P., Munafo, M. R. 2008; 10 (1): 231-240
Abstract

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.

View details for DOI 10.1080/14622200701767761

View details for Web of Science ID 000252342800025

View details for PubMedID 18188764
Chronic cigarette smoking and the microstructural integrity of white matter in healthy adults: A diffusion tensor imaging study NICOTINE & TOBACCO RESEARCH Paul, R. H., Grieve, S. M., Niaura, R., David, S. P., Laidlaw, D. H., Cohen, R., Sweet, L., Taylor, G., Clark, C. R., Pogun, S., Gordon, E. 2008; 10 (1): 137-147
Abstract

Results from recent studies suggest that chronic cigarette smoking is associated with increased white matter volume in the brain as determined by in vivo neuroimaging. We used diffusion tensor imaging to examine the microstructural integrity of the white matter in 10 chronic smokers and 10 nonsmokers. All individuals were healthy, without histories of medical or psychiatric illness. Fractional anisotropy (FA) and trace were measured in the genu, body, and splenium of the corpus callosum. FA provides a measure of directional versus nondirectional water diffusion, whereas trace provides a measure of nondirectional water diffusion. Lower FA and higher trace values are considered to reflect less brain integrity. Voxel-based morphometry was used to define volumes in each of these regions of the corpus callosum. Chronic smokers exhibited significantly higher FA in the body and whole corpus callosum and a strong trend for higher FA in the splenium compared with nonsmokers. FA did not differ between groups in the genu, and neither trace nor white matter volumes differed between groups in any of the regions of interest. When subdivided by Fagerström score (low vs. high), the low Fagerström group exhibited significantly higher FA in the body of the corpus callosum compared with the high Fagerström group and the nonsmokers. These results suggest that, among healthy adults, lower exposure to cigarette smoking is associated with increased microstructural integrity of the white matter compared with either no exposure or higher exposure. Additional studies are needed to further explore differences in white matter integrity between smokers and nonsmokers.

View details for DOI 10.1080/14622200701767829

View details for Web of Science ID 000252342800015

View details for PubMedID 18188754
Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study BRAIN IMAGING AND BEHAVIOR David, S. P., Munafo, M. R., Johansen-Berg, H., MacKillop, J., Sweet, L. H., Cohen, R. A., Niaura, R., Rogers, R. D., Matthews, P. M., Walton, R. T. 2007; 1 (3-4): 43-57
View details for DOI 10.1007/s11682-007-9004-1

View details for Web of Science ID 000207261300001
Successful Latino community partnership program for smoking cessation AMERICAN JOURNAL OF PUBLIC HEALTH David, S. P., Smith, M., Lee, C. S., Sullivan, G. 2007; 97 (8): 1348-1349
View details for DOI 10.2105/AJPH.2007.111237

View details for Web of Science ID 000255648000001

View details for PubMedID 17600240
Association of COMT Val(108/158) met genotype with smoking cessation in a nicotine replacement therapy randomized trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Johnstone, E. C., Elliot, K. M., David, S. P., Murphy, M. F., Walton, R. T., Munafo, M. R. 2007; 16 (6): 1065-1069
Abstract

We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype x treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies, but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy.

View details for DOI 10.1158/1055-9965.EPI-06-0936

View details for Web of Science ID 000247163100004

View details for PubMedID 17548664
The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: Follow-up of a randomized controlled trial NICOTINE & TOBACCO RESEARCH David, S. P., Munafo, M. R., Murphy, M. F., Walton, R. T., Johnstone, E. C. 2007; 9 (2): 225-231
Abstract

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 genotypextreatment 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.

View details for DOI 10.1080/14622200601078566

View details for Web of Science ID 000244927500007

View details for PubMedID 17365753
Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation NICOTINE & TOBACCO RESEARCH David, S. P., Brown, R. A., Papandonatos, G. D., Kahler, C. W., Lloyd-Richardson, E. E., Munafo, M. R., Shields, P. G., Lerman, C., Strong, D., McCaffery, J., Niaura, R. 2007; 9 (8): 821-833
Abstract

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 CT) 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 x bupropion interaction (B = 1.49, SE = 0.59, p = .012) [corrected] and a three-way DRD2 x bupropion x 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 x 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 x gene and gene x craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.

View details for DOI 10.1080/14622200701382033

View details for Web of Science ID 000248725500005

View details for PubMedID 17654295
Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study. Brain imaging and behavior David, S. P., Munafò, M. R., Johansen-Berg, H., Mackillop, J., Sweet, L. H., Cohen, R. A., Niaura, R., Rogers, R. D., Matthews, P. M., Walton, R. T. 2007; 1 (3-4): 43-57
Abstract

To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs-suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.

View details for PubMedID 18458752
Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials NICOTINE & TOBACCO RESEARCH David, S. P., Strong, D. R., Munafo, M. R., Brown, R. A., Lloyd-Richardson, E. E., Wileyto, P. E., Evins, E. A., Shields, P. G., Lerman, C., Niaura, R. 2007; 9 (12): 1251-1257
Abstract

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 x 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.

View details for DOI 10.1080/14622200701705027

View details for Web of Science ID 000251966100002

View details for PubMedID 18058343
Building a successful research enterprise in family medicine: the Brown experience. Medicine and health, Rhode Island David, S. P., Eaton, C. B., Culpepper, L., Goldman, R. E., Lavallee, L. K., Simmons, E. M. 2006; 89 (8): 281-284
View details for PubMedID 16967659
Fellowship training in family medicine at Brown: adding depth to breadth. Medicine and health, Rhode Island Long, R., David, S. P., Monroe, A., Shaw, J. 2006; 89 (8): 274-275
Abstract

The Brown Family Medicine fellowship programs share a common goal of nurturing the future leaders of our specialty. In a complex and demanding practice environment our fellowships have contributed to the development and propagation of an adept Family Medicine specialist. These fellowships endorse our specialty's broad approach to healthcare through addressing primary care and prevention, but also enhance the future of our field through melding the breadth of our discipline with the depth of expertise and the stewardship of responsible leadership.

View details for PubMedID 16967657
Studies of Genetic Influences on Nicotine Dependence Utilising Functional Neuroimaging. Doctoral thesis: University of Oxford, Bodleian Library, Oxford, UK. David SP. 2006
Opioid antagonists for smoking cessation COCHRANE DATABASE OF SYSTEMATIC REVIEWS David, S., Lancaster, T., Stead, L. F., Evins, A. E. 2006
Abstract

The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. Smokers 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.We searched the Cochrane Tobacco Addiction Group specialized register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in March 2006. We also contacted investigators, when possible, for information on unpublished studies.We considered randomized 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.We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was cotinine- or carbon monoxide-verified abstinence from smoking after at least six months follow up in patients smoking at baseline. Where appropriate, we performed meta-analysis using a fixed-effect model (Mantel-Haenszel odds ratios).Four trials of naltrexone met inclusion criteria for meta-analyses for long-term cessation. All four trials failed to detect a significant difference in quit rates between naltrexone and placebo. In a pooled analysis there was no significant effect of naltrexone on long-term abstinence, and confidence intervals were wide (odds ratio 1.26, 95% confidence interval 0.80 to 2.01). No trials of naloxone or buprenorphine reported long-term follow up.Based on limited data from four trials it is not possible to confirm or refute whether naltrexone helps smokers quit. The confidence intervals are compatible with both clinically significant benefit and possible negative effects of naltrexone in promoting abstinence. Data from larger trials of naltrexone are needed to settle the question of efficacy for smoking cessation.

View details for DOI 10.1002/14651858.CD003086.pub2

View details for Web of Science ID 000241386000138

View details for PubMedID 17054160
The Pharmacogenetics of Nicotine Addiction and Smoking Cessation. Chapter 21 in: Pharmacogenomics and Proteomics: Enabling the Practice of Personalized Medicine. Edited by Wong SHY, Linder MW, Valdes, Jr. R. AACC Press, Washington, DC. David SP., Munaf_ M, Walton RT. 2006; 1: 203-212.
Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: A functional magnetic resonance imaging study BIOLOGICAL PSYCHIATRY David, S. P., Munafo, M. R., Johansen-Berg, H., Smith, S. M., Rogers, R. D., Matthews, P. M., Walton, R. T. 2005; 58 (6): 488-494
Abstract

Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity.Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues.Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls.This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.

View details for DOI 10.1016/j.biopsych.2005.04.028

View details for Web of Science ID 000232296000009

View details for PubMedID 16023086
A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans JOURNAL OF NEUROSCIENCE David, S. P., Murthy, N. V., Rabiner, E. A., Munafo, M. R., Johnstone, E. C., Jacob, R., Walton, R. T., Grasby, P. M. 2005; 25 (10): 2586-2590
Abstract

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

View details for DOI 10.1523/JNEUROSCI.3769-04.2005

View details for Web of Science ID 000227528600017

View details for PubMedID 15758168
Envisaging and applying a unifying three-dimensional theoretical framework for generalist physicians. Medicine and health, Rhode Island David, S. P., Eaton, C. B., Taylor, J. S., Stamp, M. J., Cyr, M., Siegel, B., Gramling, R., Walton, R. 2004; 87 (11): 336-340
View details for PubMedID 15631301
Does providing hereditary breast cancer risk assessment support to practicing physicians decrease the likelihood of them discussing such risk with their patients? GENETICS IN MEDICINE Gramling, R., Duffy, C., David, S. 2004; 6 (6): 542-542
View details for Web of Science ID 000225180000014

View details for PubMedID 15545753
Investigating subgroups in smoking cessation treatment response: Response to Perkins NICOTINE & TOBACCO RESEARCH Munafo, M. R., Bradburn, M., Bowes, L., David, S. 2004; 6 (5): 865-867
View details for DOI 10.1080/14622200412331295942

View details for Web of Science ID 000225135700015
Are there sex differences in transdermal nicotine replacement therapy patch efficacy? A meta-analysis NICOTINE & TOBACCO RESEARCH Munafo, M., Bradburn, M., Bowes, L., David, S. 2004; 6 (5): 769-776
Abstract

Smoking-related death and disability rates for women have risen sharply recently. Despite lower smoking cessation success rates for women using behavioral therapies, data are limited on whether specific pharmacological therapies are equally efficacious in men and women. Using meta-analytic techniques, we examined whether significant differences in therapeutic efficacy of nicotine replacement therapy (NRT) for smoking cessation exist by sex. Out of the 31 randomized clinical trials of NRT that met inclusion criteria, 11 contributed to the analysis. The odds ratios for NRT vs. placebo were derived from each trial separately by sex for males and females, and these ratios were combined to give a pooled estimate of the effect of sex in response to NRT. NRT was effective at all time points in men (< 6 months: OR = 2.05, 95% CI= 1.61-2.60; 6 months: OR = 1.98, 95% CI = 1.51-2.60; 12 months: OR = 1.86, 95% CI = 1.39-2.50) and women (< 6 months: OR = 2.09, 95% CI = 1.65-2.65; 6 months, OR = 1.52, 95% CI = 1.17-1.98; 12 months: OR = 1.63, 95% CI = 1.22-2.18). At all time points, no significant difference was observed between sexes (< 6 months: OR = .97, 95% CI = .69-1.36; 6 months: OR = 1.33, 95% CI = .91-1.95; 12 months: OR = 1.21, 95% CI = .79-1.84). The results of this meta-analysis do not support the hypothesis that NRT has higher therapeutic efficacy for men than women.

View details for DOI 10.1080/1462200410001696556

View details for Web of Science ID 000225135700004

View details for PubMedID 15700912
Pharmacogenetics PRIMARY CARE David, S. P. 2004; 31 (3): 543-?
Abstract

This article provides an introduction to the discipline of pharmacogenetics and discusses the implications of pharmacogenetics research for primary care practice. Examples are given of how genetic information can predict and inform; drug interactions influencing drug efficacy, metabolism, dosing, and toxicity. Caveats on the need for vigilance in the interpretation of pharmacogenetics studies are discussed briefly, together with the need for a convergence of biomolecular research, translational research, education,and policy to promote evidence-based genetic medicine.

View details for DOI 10.1016/j.pop.2004.04.009

View details for Web of Science ID 000224051500008

View details for PubMedID 15331247
Evaluation of an educational intervention for medical students to promote competency in social and community determinants of health. ABSAME David SP., Taylor JS, Monroe A, Goldman R, Green AR, Boss JD, Sagaties D. 2004; 10 (2): 68-73.
Investigating subgroups in smoking cessation treatment response: Response to Perkins. Nicotine Tob Res Munaf_ M, Bradburn M, Bowes L, David S. 2004; 6 (5): 865-867
Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome? NICOTINE & TOBACCO RESEARCH David, S. P., Niaura, R., Papandonatos, G. D., Shadel, W. G., Burkholder, G. J., Britt, D. M., Day, A., Stumpff, J., Hutchison, K., Murphy, M., Johnstone, E., Griffiths, S. E., Walton, R. T. 2003; 5 (6): 935-942
Abstract

Bupropion hydrochloride is effective in promoting long-term abstinence from smoking and may reduce risk for relapse through attenuation of withdrawal symptoms and craving. Bupropion is a weak dopamine reuptake inhibitor, and individual genetic variation in the dopamine D2 receptor has been associated with nicotine dependence in case-control studies. Thirty smokers were randomly assigned to bupropion or placebo and interviewed using the Minnesota Nicotine Withdrawal Scale on two occasions: prior to starting medication and after 14 days on bupropion or placebo. The individual symptoms of craving, irritability, and anxiety were significantly reduced in the bupropion group, whereas no withdrawal symptoms were diminished in the placebo group. Within the bupropion group, subgroup analyses with stratification by genotype demonstrated that craving, irritability, and anxiety were significantly attenuated only among subjects with DRD2-Taq1 A2/A2 genotypes. In the DRD2-Taq1 A1/A1 and A1/A2 groups, no significant reduction was seen in any individual symptom of the nicotine withdrawal syndrome. These data suggest that bupropion attenuates specific symptoms of the nicotine withdrawal syndrome and that this effect may be modified by genotype for the dopamine D2 receptor.

View details for DOI 10.1080/14622200310001615295

View details for Web of Science ID 000188241000016

View details for PubMedID 14668077
Should we offer routine breast cancer screening with mammography? AMERICAN FAMILY PHYSICIAN David, S. P. 2003; 68 (2): 260-262
View details for Web of Science ID 000184320500006

View details for PubMedID 12892345
Genetic susceptibility to breast cancer: Teaching points FAMILY MEDICINE Gramling, R., David, S. 2003; 35 (7): 466-468
View details for Web of Science ID 000184126400005

View details for PubMedID 12861454
Comment on "The public health implications of smoking-induced decreased serum and red blood cell folate levels" NICOTINE & TOBACCO RESEARCH David, S. P., Eaton, C. B. 2003; 5 (3): 397-399
View details for DOI 10.1080/1462220031000094123

View details for Web of Science ID 000185022100013

View details for PubMedID 12791535
Are family physicians willing to use pharmacogenetics for smoking cessation therapy? FAMILY MEDICINE Stamp, M. J., David, S. P. 2003; 35 (2): 83-83
View details for Web of Science ID 000180976200002

View details for PubMedID 12607800
Should we prescribe antibiotics for acute conjunctivitis? American family physician David, S. P. 2002; 66 (9): 1649-1650
View details for PubMedID 12449262
Should we use multiple risk factor interventions for the primary prevention of coronary heart disease? AMERICAN FAMILY PHYSICIAN David, S. P. 2002; 66 (2): 245-246
View details for Web of Science ID 000177110500006

View details for PubMedID 12152959
No association between functional catechol O-methyl transferase 1947A > G polymorphism and smoking initiation, persistent smoking or smoking cessation PHARMACOGENETICS David, S. P., Johnstone, E., Griffiths, S. E., Murphy, M., Yudkin, P., Mant, D., Walton, R. 2002; 12 (3): 265-268
Abstract

Nicotine stimulates dopamine release and activates dopaminergic reward neurones in central pathways giving rise to dependence. Catechol O-methyl transferase (COMT) inactivates extraneuronally released dopamine and is present in dopaminergic brain regions. A functional polymorphism (COMT 1947A>G) resulting in increased enzyme activity has been associated with alcoholism and polysubstance abuse. We examined the relationship between the COMT 1947A>G polymorphism and smoking initiation, smoking persistence and smoking cessation. We genotyped 266 current smokers, 270 ex-smokers and 265 lifetime non-smokers (never smokers), matched for age and gender, for the COMT 1947A>G polymorphism. Smoking status was ascertained by self-report. There was no difference in genotype frequencies between never smokers and ever smokers (current + ex-smokers); between non-smokers (never + ex-smokers) and current smokers; or between current smokers and ex-smokers. These data suggest that the COMT 1947A>G polymorphism is not associated with smoking initiation, smoking persistence or smoking cessation.

View details for Web of Science ID 000175057600011

View details for PubMedID 11927842
Should we recommend nicotine replacement therapy? AMERICAN FAMILY PHYSICIAN David, S. P. 2001; 63 (11): 2245-2247
View details for Web of Science ID 000169272700019

View details for PubMedID 11417777
A civic role for physicians in the promotion of global tobacco control FAMILY PRACTICE David, S. P. 2001; 18 (1): 107-107
View details for Web of Science ID 000167146700020

View details for PubMedID 11145639
Social marketing: Application to medical education ANNALS OF INTERNAL MEDICINE David, S. P., Greer, D. S. 2001; 134 (2): 125-127
Abstract

Medical education is often a frustrating endeavor, particularly when it attempts to change practice behavior. Traditional lecture-based educational methods are limited in their ability to sustain concentration and interest and to promote learner adherence to best-practice guidelines. Marketing techniques have been very effective in changing consumer behavior and physician behavior. However, the techniques of social marketing-goal identification, audience segmentation, and market research-have not been harnessed and applied to medical education. Social marketing can be applied to medical education in the effort to go beyond inoculation of learners with information and actually change behaviors. The tremendous potential of social marketing for medical education should be pilot-tested and systematically evaluated.

View details for Web of Science ID 000166356000006

View details for PubMedID 11177316
Opioid antagonists for smoking cessation. Cochrane database of systematic reviews David, S., Lancaster, T., Stead, L. F. 2001: CD003086-?
Abstract

The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. Smokers 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.We searched the Cochrane Tobacco Addiction Group trials register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of Medline using '"Narcotic antagonists" and smoking terms in March 2001. We also contacted, when possible, investigators for information on unpublished studies.We considered randomized controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included only trials reporting data on abstinence of a minimum of 6 months in the meta-analyses. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psychobiological mediating variables associated with nicotine dependence.We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was cotinine or carbon monoxide verified abstinence from smoking after at least six months follow-up in patients smoking at baseline. Where appropriate, we performed meta-analysis using a fixed effects model (Peto method).Two trials of naltrexone met inclusion criteria for meta-analyses for long term cessation. Both trials failed to detect a significant difference in quit rates between naltrexone and placebo. In a pooled analysis there was no significant effect of naltrexone on long-term abstinence, and confidence intervals were wide (OR 1.34, 95% CI 0.49,3.63). No trials of naloxone or buprenorphine reported long term follow-upBased on limited data from two trials it is not possible to confirm or refute whether naltrexone helps smokers quit. The confidence intervals are compatible with both clinically significant benefit and possible negative effects of naltrexone in promoting abstinence. Data from larger trials of naltrexone are needed to settle the question of efficacy for smoking cessation.

View details for PubMedID 11687036
Smoking cessation for the primary care physician. Prim Care Rep. David SP. 2001; 7 (24): 211-221.
Media advocacy for the office-based teacher of family medicine FAMILY MEDICINE David, S. P. 2001; 33 (1): 16-18
View details for Web of Science ID 000166289600007

View details for PubMedID 11199903
International tobacco control: A focus group study of US anti-tobacco activists JOURNAL OF PUBLIC HEALTH POLICY David, S., DeJong, W., Resnick, N. 2001; 22 (4): 415-428
Abstract

Massachusetts tobacco control activists participated in focus groups to explore their knowledge, beliefs, and attitudes regarding international tobacco control. Initially, each of three focus groups ranked this issue at or near the bottom of important tobacco control issues. Participants ranked ten message concepts for their ability to motivate politically active Americans to contact a government representative about international tobacco issues. The top four message concepts dealt with deliberate marketing of cigarettes to children, dramatic increases in global mortality due to smoking, American hypocrisy in being the world's largest tobacco exporter, and use of overseas profits to finance youth-oriented marketing in the U.S. The rankings revealed little initial concern about U.S. diplomatic pressure to force foreign nations to open up their markets to American tobacco products. Yet during the subsequent discussion this was among the message concepts the generated the most outrage. This suggests that international tobacco control issues would resonate among U.S. opinion leaders once the facts were presented to them through a media advocacy campaign.

View details for Web of Science ID 000172987300003

View details for PubMedID 11787307
Reflections from a rotation in Cambridge, England FAMILY MEDICINE David, S. P. 2000; 32 (5): 310-312
View details for Web of Science ID 000086882900009

View details for PubMedID 10820671
The Transatlantic Conference on Tobacco (TACT): a model for international tobacco policy activism. Journal of cancer education David, S. P. 1998; 13 (4): 253-254
Abstract

Smoking prevalence rates are alarmingly high in developing countries at a time when the United States and the United Kingdom are mobilizing domestic anti-smoking forces. A resident at Dartmouth-Hitchcock Medical Center established an American-British partnership to promote international tobacco policy activism.The program assembled a coalition of physicians and public health experts from the two countries and provided them with an Internet-based chat resource.The coalition utilized Internet resources to follow international trends in tobacco use policies and agreed to meet bimonthly through the site to promote anti-smoking activism.This report introduces a novel approach to international anti-tobacco policy activism. It provides a model that is transportable to other institutions and other public health measures.

View details for PubMedID 9883786

Conference Proceedings

CHRONIC STRESS & SALIVARY BIOMARKERS Mallick, A., Bergen, A., Nishita, D., Wei, X., Michel, M., David, S. P., Swan, G. E., REID, M. W., Simons, A. D., Andrews, J. LIPPINCOTT WILLIAMS & WILKINS. 2013: 141-141
View details for Web of Science ID 000312657900115

Clinical Associate Professor, Medicine - General Medical Disciplines

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