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1.  The DRD4 Exon III VNTR, Bupropion, and Associations With Prospective Abstinence 
Nicotine & Tobacco Research  2012;15(7):1190-1200.
Introduction:
DRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive–behavioral mood management therapy.
Methods:
We used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies. VNTR genotypes were coded with the long allele dominant resulting in 4 analysis categories. Covariates included demographics, dependence measures, depressive symptoms, and genetic ancestry. We also performed genotype-stratified secondary analyses.
Results:
We observed significant effects of time in longitudinal analyses of both abstinence outcomes, of treatment in individuals with VNTR long allele genotypes for both abstinence outcomes, and of covariates in some analyses. We observed non-significantly larger differences in active versus placebo effect sizes in individuals with VNTR long allele genotypes than in individuals without the VNTR long allele, in the directions previously reported.
Conclusions:
VNTR by treatment interaction differences between these and previous analyses may be attributable to insufficient size of the replication sample. Analyses of multiple randomized clinical trials will enable identification and validation of factors mediating treatment response.
doi:10.1093/ntr/nts245
PMCID: PMC3682839  PMID: 23212438
2.  The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex 
Background
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure.
Methods
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163).
Results
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males.
Conclusions
In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.
Impact
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
doi:10.1158/1055-9965.EPI-12-1234-T
PMCID: PMC3617060  PMID: 23371292
Tobacco; Cotinine; CYP2A6; Polycyclic aromatic hydrocarbons; NNAL
3.  Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking 
Stephens, Sarah H. | Hartz, Sarah M. | Hoft, Nicole R. | Saccone, Nancy L. | Corley, Robin C. | Hewitt, John K. | Hopfer, Christian J. | Breslau, Naomi | Coon, Hilary | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Han, Younghun | Hansel, Nadia N. | Jiang, Chenhui | Korhonen, Tellervo | Lind, Penelope A. | Liu, Jason | Lyytikäinen, Leo-Pekka | Michel, Martha | Shaffer, John R. | Short, Susan E. | Sun, Juzhong | Teumer, Alexander | Thompson, John R. | Vogelzangs, Nicole | Vink, Jacqueline M. | Wenzlaff, Angela | Wheeler, William | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri H. | Benjamin, Daniel J. | Bergen, Andrew W. | Broms, Ulla | Cesarini, David | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gillespie, Nathan A. | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Heikkilä, Kauko | Hickie, Ian B. | Hottenga, Jouke Jan | Jousilahti, Pekka | Kaakinen, Marika | Kähönen, Mika | Koellinger, Philipp D. | Kittner, Stephen | Konte, Bettina | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Murray, Tanda | Nauck, Matthias | North, Kari E. | Paré, Peter D. | Pergadia, Michele | Ruczinski, Ingo | Salomaa, Veikko | Viikari, Jorma | Willemsen, Gonneke | Barnes, Kathleen C. | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Edenberg, Howard J. | Francks, Clyde | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Johannesson, Magnus | Kendler, Kenneth S. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Marazita, Mary L. | Marchini, Jonathan | Mitchell, Braxton D. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Schwartz, Ann G. | Shete, Sanjay | Spitz, Margaret | Swan, Gary E. | Völzke, Henry | Veijola, Juha | Wei, Qingyi | Amos, Chris | Cannon, Dale S. | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J. | Ehringer, Marissa A.
Genetic epidemiology  2013;37(8):846-859.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
doi:10.1002/gepi.21760
PMCID: PMC3947535  PMID: 24186853
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
4.  Nicotinic Acetylcholine Receptor Variation and Response to Smoking Cessation Therapies 
Pharmacogenetics and genomics  2013;23(2):94-103.
Objective
Evaluate nicotinic acetycholine receptor (nAChR) single nucleotide polymorphism (SNP) association with seven day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies (RCTs) in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.
Methods
We quantified association of four SNPs at three nAChRs with abstinence in eight RCTs. Participants were 2,633 outpatient treatment-seeking, self-identified European ancestry individuals smoking ≥10 cigarettes per day, recruited via advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment (EOT) and six month (6MO) abstinence, with demographic, behavioral and genetic covariates.
Results
“Risk” alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the placebo pharmacotherapy group (PG) at 6MO [for rs588765 OR (95%CI) 0.41 (0.17–0.99)], and at EOT and at 6MO [for rs1051730, 0.42 (0.19–0.93) and 0.31 (0.12–0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765 2.07 (1.11–3.87) and for rs1051730 2.54 (1.29–4.99)]. We observed significant heterogeneity in rs1051730 effects (F=2.48, P=0.021) between PGs.
Conclusions
chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with placebo treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.
doi:10.1097/FPC.0b013e32835cdabd
PMCID: PMC3563676  PMID: 23249876
logistic regression; mediation analysis; nAChR variation; nicotine dependence; pharmacotherapy; randomized clinical trials
5.  Pharmacogenetic Smoking Cessation Intervention in a Health Care Setting: A Pilot Feasibility Study 
Nicotine & Tobacco Research  2012;15(2):518-526.
Introduction:
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.
Methods:
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).
Results:
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.
Conclusions:
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.
doi:10.1093/ntr/nts173
PMCID: PMC3611995  PMID: 22949583
6.  Varenicline for Smoking Cessation: Nausea Severity and Variation in Nicotinic Receptor Genes 
The Pharmacogenomics Journal  2011;12(4):349-358.
This study evaluated association between common and rare sequence variants in 10 nicotinic acetylcholine receptor subunit genes and the severity of nausea 21 days after initiating the standard, FDA-approved varenicline regimen for smoking cessation. Included in the analysis were 397 participants from a randomized clinical effectiveness trial with complete clinical and DNA resequencing data (mean age = 49.2 years; 68.0% female). Evidence for significant association between common sequence variants in CHRNB2 and nausea severity was obtained after adjusting for age, gender, and correlated tests (all PACT<.05). Individuals with the minor allele of CHRNB2 variants experienced less nausea than did those without the minor allele, consistent with previously reported findings for CHRNB2 and the occurrence of nausea and dizziness as a consequence of first smoking attempt in adolescents, and with the known neurophysiology of nausea. As nausea is the most common reason for discontinuance of varenicline, further pharmacogenetic investigations are warranted.
doi:10.1038/tpj.2011.19
PMCID: PMC3405554  PMID: 21606948
varenicline; nausea; smoking cessation; adherence
7.  Chronic psychosocial stressors and salivary biomarkers in emerging adults 
Psychoneuroendocrinology  2011;37(8):1158-1170.
Summary
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.
doi:10.1016/j.psyneuen.2011.11.010
PMCID: PMC3774595  PMID: 22172638
Human; Saliva; Gene expression; IL8; qPCR
8.  COMPARATIVE DYNAMICS OF FOUR SMOKING WITHDRAWAL SYMPTOM SCALES 
Addiction (Abingdon, England)  2012;107(8):1501-1511.
Aims
Examine the association of person-specific trajectories of withdrawal symptoms of urge-to-smoke, negative affect, physical symptoms, and hunger during the first 7 days after smoking cessation with abstinence at end of treatment (EOT) and 6 months.
Design
Hierarchical Linear Modeling (HLM) was used to model person-specific trajectory parameters (level, slope, curvature and volatility) for withdrawal symptoms.
Setting
University-based smoking cessation trials.
Participants
Treatment seeking smokers in clinical trials of transdermal nicotine versus nicotine spray (n=514) and bupropion versus placebo (n=421)
Measurements
Self-reported withdrawal symptoms for 7 days after the planned quit date, and 7 day point prevalence and continuous abstinence at EOT and 6 months.
Findings
In regressions that included trajectory parameters for one group of withdrawal symptoms, both urge-to-smoke and negative affect were predictive of abstinence while physical symptoms and hunger were generally not predictive. In stepwise regressions that included the complete set of trajectory parameters across withdrawal symptoms (for urge-to-smoke, negative affect, physical symptoms, and hunger), with a single exception, only the trajectory parameters for urge-to-smoke were predictive. Area under the Receiver Operator Characteristic curve was 0.594 for covariates alone, and 0.670 for covariates plus urge-to-smoke trajectory parameters.
Conclusion
Among a number of different withdrawal symptoms (urge-to-smoke, negative affect, physical symptoms, and hunger) urge-to-smoke trajectory parameters (level, slope, and volatility) over the first 7 days of smoking cessation show the strongest prediction of both short and long term relapse. Other withdrawal symptoms increase the predictive ability by negligible amounts.
doi:10.1111/j.1360-0443.2012.03838.x
PMCID: PMC3394903  PMID: 22321019
smoking cessation; withdrawal symptoms; urge-to-smoke; negative affect; physical symptoms; hunger; nicotine replacement therapy; bupropion
9.  Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers 
Hartz, Sarah M. | Short, Susan E. | Saccone, Nancy L. | Culverhouse, Robert | Chen, LiShiun | Schwantes-An, Tae-Hwi | Coon, Hilary | Han, Younghun | Stephens, Sarah H. | Sun, Juzhong | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Geller, Frank | Guđbjartsson, Daniel | Hansel, Nadia N. | Jiang, Chenhui | Keskitalo-Vuokko, Kaisu | Liu, Zhen | Lyytikäinen, Leo-Pekka | Michel, Martha | Rawal, Rajesh | Hum, Sc | Rosenberger, Albert | Scheet, Paul | Shaffer, John R. | Teumer, Alexander | Thompson, John R. | Vink, Jacqueline M. | Vogelzangs, Nicole | Wenzlaff, Angela S. | Wheeler, William | Xiao, Xiangjun | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri | Bennett, Siiri | Bergen, Andrew W. | Boyd, Heather A. | Broms, Ulla | Campbell, Harry | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle M. | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Hayward, Caroline | Heikkilä, Kauko | Lic, Phil | Hewitt, John K. | Hottenga, Jouke Jan | Jensen, Majken K. | Jousilahti, Pekka | Kaakinen, Marika | Kittner, Steven J. | Konte, Bettina | Korhonen, Tellervo | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Muley, Thomas | Murray, Tanda | Nauck, Matthias | North, Kari | Pergadia, Michele | Polasek, Ozren | Ramos, Erin M. | Ripatti, Samuli | Risch, Angela | Ruczinski, Ingo | Rudan, Igor | Salomaa, Veikko | Schlessinger, David | Styrkársdóttir, Unnur | Terracciano, Antonio | Uda, Manuela | Willemsen, Gonneke | Wu, Xifeng | Abecasis, Goncalo | Barnes, Kathleen | Bickeböller, Heike | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Duan, Jubao | Edenberg, Howard J. | Francks, Clyde | Gejman, Pablo V. | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Viikari, Jorma | Kähönen, Mika | Kendler, Kenneth S. | Lehtimäki, Terho | Levinson, Douglas F. | Marazita, Mary L. | Marchini, Jonathan | Melbye, Mads | Mitchell, Braxton D. | Murray, Jeffrey C. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Sanders, Alan R. | Schwartz, Ann G. | Shete, Sanjay | Shi, Jianxin | Spitz, Margaret | Stefansson, Kari | Swan, Gary E. | Thorgeirsson, Thorgeir | Völzke, Henry | Wei, Qingyi | Wichmann, H.-Erich | Amos, Christopher I. | Breslau, Naomi | Cannon, Dale S. | Ehringer, Marissa | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Stitzel, Jerry A. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J.
Archives of general psychiatry  2012;69(8):854-860.
Context
Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
Objective
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Data Sources
Primary data.
Study Selection
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Data Extraction
Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Data Synthesis
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01).
Conclusion
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
doi:10.1001/archgenpsychiatry.2012.124
PMCID: PMC3482121  PMID: 22868939
10.  DRD1 Associations with Smoking Abstinence Across Slow and Normal Nicotine Metabolizers 
Pharmacogenetics and Genomics  2012;22(7):551-554.
Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence, but further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cutoff). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system. Gene × NMR interaction P-values were adjusted for multiple correlated tests, and we used a Bonferroni-corrected α-level of 0.004 to determine system-wide significance. Three SNPs in DRD1 (rs11746641, rs2168631, rs11749035) had significant interactions (0.001 ≤ adjusted P-values ≤ 0.004), with increased odds of abstinence within slow metabolizers (ORs=3.1–3.5, 95% CI 1.7–6.7). Our findings support the role of DRD1 in nicotine dependence, and identify genetic and nicotine metabolism profiles that may interact to impact nicotine dependence.
doi:10.1097/FPC.0b013e3283539062
PMCID: PMC3376177  PMID: 22495174
Genetic association studies; heterogeneity; smoking abstinence; nicotine metabolism; nicotine metabolite ratio; DRD1
11.  Pain Sensitivity and Opioid Analgesia: A Pharmacogenomic Twin Study 
Pain  2012;153(7):1397-1409.
Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the muopioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12–60% of the observed response variance. Significant familial effects accounting for 24–32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.
doi:10.1016/j.pain.2012.02.022
PMCID: PMC3377769  PMID: 22444188
12.  Aversive and Reinforcing Opioid Effects: A Pharmacogenomic Twin Study 
Anesthesiology  2012;117(1):22-37.
Background
The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual’s susceptibility to adverse opioid effects is essential to identify patients at risk.
Methods
A classical twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses; all secondary outcomes of a larger data set. One hundred and twenty one twin pairs were recruited in a single occasion, randomized, double-blind and placebo controlled study. The mu-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated.
Results
Significant heritability was detected for respiratory depression (30%), nausea (59%) and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, gender, race, ethnicity, education, mood and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness.
Conclusions
This study demonstrates that large scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses.
doi:10.1097/ALN.0b013e31825a2a4e
PMCID: PMC3428265  PMID: 22713632
13.  Gender Stratified Gene and Gene–Treatment Interactions in Smoking Cessation 
The pharmacogenomics journal  2011;12(6):521-532.
We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni corrected α-level of 5 × 10−4 to determine system-wide significance. Four SNPs (rs12021667, rs12027267, rs6702335, rs12039988; r2>0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (OR=0.5; 95% CI 0.3–0.6) at end of treatment (adjusted P<6 × 10−5). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P=3.9 × 10−5); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR=0.04; 95% CI 0.01–0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.
doi:10.1038/tpj.2011.30
PMCID: PMC3208134  PMID: 21808284
Genetic association studies; heterogeneity; smoking cessation
14.  Behavioral Counseling and Varenicline Treatment for Smoking Cessation 
Background
Smoking remains the primary preventable cause of death and illness in the U.S. Effective, convenient treatment programs are needed to reduce smoking prevalence.
Purpose
This study compared the effectiveness of three modalities of a behavioral smoking-cessation program in smokers using varenicline.
Methods
Current treatment seeking smokers (n=1202) were recruited from a large healthcare organization between October 2006 and October 2007. Eligible participants were randomized to one of three smoking-cessation interventions: web-based counseling (n=401), proactive telephone-based counseling (PTC; n=402), or combined PTC and web counseling (n=399). All participants received a standard 12-week FDA-approved course of varenicline. Self-report determined the primary outcomes (7-day point prevalent abstinence at 3- and 6-month follow-up), the number of days varenicline was taken, and treatment-related symptoms. Behavioral measures determined utilization of both the web- and phone-based counseling.
Results
Intent-to-treat analyses revealed relatively high percentages of abstinence at 3 months (38.9%, 48.5%, 43.4%) and at 6 months (30.7%, 34.3%, 33.8%) for the web, PTC, and PTC web groups, respectively. The PTC group had a significantly higher percentage of abstinence than the web group at 3 months, OR=1.48, 95% CI 1.12–1.96, but no between-group differences in abstinence outcomes were seen at 6 months.
Conclusions
Phone counseling had greater treatment advantage for early cessation and appeared to increase medication adherence, but the absence of differences at 6 months suggests that any of the interventions hold promise when used in conjunction with varenicline.
doi:10.1016/j.amepre.2010.01.024
PMCID: PMC2879135  PMID: 20409497
15.  Longitudinal genetic analysis of brain volumes in normal elderly male twins 
Neurobiology of Aging  2010;33(4):636-644.
This study investigated the role of genetic and environmental influences on individual differences in brain volumes measured at two time points in normal elderly males from the National Heart, Lung, and Blood Institute Twin Study. The MRI scans were conducted four years apart on 33 monozygotic and 33 dizygotic male twin pairs, aged 68 to 77 years when first scanned. Volumetric measures of total brain and total cerebrospinal fluid were significantly heritable at baseline (over 70%). For both volumes genetic influences at follow-up were entirely accounted for by genetic influences at baseline, suggesting that the same genetic factors influence variability in brain volume at each time of assessment. Variability in 4-year volume change was due to shared and individual-specific environmental influences. There was little evidence for heritable influences on change measures. These results suggest that variation in longitudinal change of some brain volume measures may have different underlying genetic and environmental architecture from variation in repeat cross-sectional measures, which could have implications for intervention strategies for age-related illness associated with brain morphology. The results of this study are discussed in the context of the small sample size and associated limitations of statistical power.
doi:10.1016/j.neurobiolaging.2010.06.002
PMCID: PMC2970700  PMID: 20630620
twins; volumetric MRI; longitudinal; aging
16.  Genome-wide Linkage of Cotinine Pharmacokinetics Suggests Candidate Regions on Chromosomes 9 and 11 
Characterizing cotinine pharmacokinetics is a useful way to study nicotine metabolism because the same liver enzyme is primarily responsible for the metabolism of both, and the clearances of nicotine and cotinine are highly correlated. We conducted a whole-genome linkage analysis to search for candidate regions influencing quantitative variation in cotinine pharmacokinetics in a large-scale pharmacokinetic study with 61 families containing 224 healthy adult participants. The strongest linkage signal was identified at 135 cM of chromosome 9 with LOD=2.81 and P=0.0002; two other suggestive linkage peaks appear at 31.4 and 73.5 cM of chromosome 11 with LOD=1.96 (P=0.0013) and 1.94 (P=0.0014). The confidence level of the linkage between the three genome regions and cotinine pharmacokinetics is statistically significant with a genome-wide empirical probability of P=0.029.
doi:10.1002/ajmg.b.30859
PMCID: PMC2693302  PMID: 18785207
pharmacokinetics; nicotine; dependence; linkage analysis
17.  GENETIC AND ENVIRONMENTAL INFLUENCES ON THE RATIO OF 3’HYDROXYCOTININE TO COTININE IN PLASMA AND URINE 
Pharmacogenetics and genomics  2009;19(5):388-398.
Objectives
The ratio of trans-3’hydroxycotinine/cotinine (3HC/COT) is a marker of CYP2A6 activity, an important determinant of nicotine metabolism. This analysis sought to conduct a combined genetic epidemiologic and pharmacogenetic investigation of the 3HC/COT ratio in plasma and urine.
Methods
One hundred thirty nine twin pairs (110 monozygotic [MZ] and 29 dizygotic [DZ]) underwent a 30-minute infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, followed by an 8-hour in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine, and metabolites. DNA was genotyped to confirm zygosity and for variation in the gene for the primary nicotine metabolic enzyme, CYP2A6 (variants genotyped: *1B, *1×2, *2, *4, *9, *12). Univariate biometric analyses quantified genetic and environmental influences on each measure in the presence and absence of covariates, including measured CYP2A6 genotype.
Results
There was a substantial amount of variation in the free 3HC/COT ratio in plasma (6 hours post-infusion) attributable to additive genetic influences (67.4%, 95% CI = 55.9–76.2%). The heritability estimate was reduced to 61.0% and 49.4%, respectively, after taking into account the effect of covariates and CYP2A6 genotype. In urine (collected over 8 hours), the estimated amount of variation in the 3HC/COT ratio attributable to additive genetic influences was smaller (47.2%, 95% CI = 0–67.2%) and decreased to 44.6% and 42.0% after accounting for covariates and genotype.
Conclusions
Additive genetic factors are prominent in determining variation in plasma 3HC/COT variation but less so in determining variation in urine 3HC/COT.
doi:10.1097/FPC.0b013e32832a404f
PMCID: PMC2849278  PMID: 19300303
pharmacogenetics; nicotine; cotinine; metabolism; CYP2A6; twins; genetics; heritability
18.  Dopamine genes and nicotine dependence in treatment seeking and community smokers 
We utilized a cohort of 828 treatment seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent’s smoking behavior. 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex and study site. SNP P values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3 and NR4A2 SNPs with adjusted P values < 0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic and literature analyses. Each independent signal among the top-ranked SNPs accounted for ~1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
doi:10.1038/npp.2009.52
PMCID: PMC3558036  PMID: 19494806
dopamine transporter; Fagerström Test for Nicotine Dependence; single nucleotide polymorphism; candidate gene association scan; gene-gene interaction
19.  Test-Retest Reliability of Web-Based Retrospective Self-Report of Tobacco Exposure and Risk 
Background
Retrospectively collected data about the development and maintenance of behaviors that impact health are a valuable source of information. Establishing the reliability of retrospective measures is a necessary step in determining the utility of that methodology and in studying behaviors in the context of risk and protective factors.
Objective
The goal of this study was to examine the reliability of self-report of a specific health-affecting behavior, tobacco use, and its associated risk and protective factors as examined with a Web-based questionnaire.
Methods
Core tobacco use and risk behavior questions in the Lifetime Tobacco Use Questionnaire—a closed, invitation-only, password-controlled, Web-based instrument—were administered at a 2-month test-retest interval to a convenience sample of 1229 respondents aged 18 to 78 years. Tobacco use items, which covered cigarettes, cigars, smokeless tobacco, and pipe tobacco, included frequency of use, amount used, first use, and a pack-years calculation. Risk-related questions included family history of tobacco use, secondhand smoke exposure, alcohol use, and religiosity.
Results
Analyses of test-retest reliability indicated modest (.30 to .49), moderate (.50 to .69), or high (.70 to 1.00) reliability across nearly all questions, with minimal reliability differences in analyses by sex, age, and income grouping. Most measures of tobacco use history showed moderate to high reliability, particularly for age of first use, age of first weekly and first daily smoking, and age at first or only quit attempt. Some measures of family tobacco use history, secondhand smoke exposure, alcohol use, and religiosity also had high test-retest reliability. Reliability was modest for subjective response to first use.
Conclusions
The findings reflect the stability of retrospective recall of tobacco use and risk factor self-report responses in a Web-questionnaire context. Questions that are designed and tested with psychometric scrutiny can yield reliable results in a Web setting.
doi:10.2196/jmir.1248
PMCID: PMC2762856  PMID: 19674962
Tobacco smokers; retrospective studies; psychometrics
20.  Nicotine withdrawal sensitivity, linkage to chr6q26, and association of OPRM1 SNPs in the SMOking in FAMilies (SMOFAM) sample 
Background
Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms.
Methods
The objectives of these analyses are: a) to assess the influence of nicotine withdrawal sensitivity on relapse, b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and c) explore family-based association of single nucleotide polymorphism (SNPs) at the mu opioid receptor (MOR) candidate gene (OPRM1) to nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores.
Results
An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, OR=1.25, 95% confidence interval, 95%CI=1.10,1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family based association test (FBAT) with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P-values<0.05 and false discovery rate Q-values<0.06.
Conclusion
An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs was found with Rasch modeled nicotine withdrawal sensitivity score in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.
doi:10.1158/1055-9965.EPI-09-0960
PMCID: PMC3536862  PMID: 19959688
21.  Asthma Discordance in Twins Is Linked to Epigenetic Modifications of T Cells 
PLoS ONE  2012;7(11):e48796.
T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.
doi:10.1371/journal.pone.0048796
PMCID: PMC3511472  PMID: 23226205
22.  Sensitivity to Secondhand Smoke Exposure Predicts Future Smoking Susceptibility 
Pediatrics  2011;128(2):254-262.
OBJECTIVE:
Susceptibility to cigarette smoking in tobacco-naive youth is a strong predictor of smoking initiation. Identifying mechanisms that contribute to smoking susceptibility provide information about early targets for smoking prevention. This study investigated whether sensitivity to secondhand smoke exposure (SHSe) contributes to smoking susceptibility.
PARTICIPANTS AND METHODS:
Subjects were high-risk, ethnically diverse 8- to 13-year-old subjects who never smoked and who lived with at least 1 smoker and who participated in a longitudinal SHSe reduction intervention trial. Reactions (eg, feeling dizzy) to SHSe were assessed at baseline, and smoking susceptibility was assessed at baseline and 3 follow-up measurements over 12 months. We examined the SHSe reaction factor structure, association with demographic characteristics, and prediction of longitudinal smoking susceptibility status.
RESULTS:
Factor analysis identified “physically unpleasant” and “pleasant” reaction factors. Reported SHSe reactions did not differ across gender or family smoking history. More black preteens reported feeling relaxed and calm, and fewer reported feeling a head rush or buzz compared with non-Hispanic white and Hispanic white counterparts. Longitudinally, 8.5% of subjects tracked along the trajectory for high (versus low) smoking susceptibility. Reporting SHSe as “unpleasant or gross” predicted a 78% reduction in the probability of being assigned to the high–smoking susceptibility trajectory (odds ratio: 0.22 [95% confidence interval: 0.05–0.95]), after covariate adjustment.
CONCLUSIONS:
Assessment of SHSe sensitivity is a novel approach to the study of cigarette initiation etiology and informs prevention interventions.
doi:10.1542/peds.2010-3156
PMCID: PMC3146357  PMID: 21746728
secondhand smoke; sensitivity; smoking susceptibility; trajectories; preteens
23.  Children of Persons With Alzheimer Disease 
Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent’s fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.
doi:10.1097/WAD.0b013e31816653ac
PMCID: PMC3377487  PMID: 18317242
Alzheimer disease offspring; risk factors
24.  Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases 
PLoS Computational Biology  2012;8(6):e1002538.
Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P = 1.3×10−10) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P = 1.7×10−4, 1.8×10−4, and 2.2×10−4 respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.
Author Summary
The mechanisms underlying pain are incompletely understood, and are hard to study due to the subjective and complex nature of pain. From a genetics perspective, the discovery of genes relevant for the processing of pain in humans has been slow and genome-wide association studies have not been successful in yielding significantly associated variants. Targeted approaches examining specific candidate genes may be more promising. We present a novel integrative approach that combines publicly available molecular data and automatically extracted knowledge regarding pain contained in the literature to assist the discovery of novel pain genes. We prospectively validated this approach by demonstrating a significant association between several newly identified pain gene candidates and sensitivity to cold pressor pain.
doi:10.1371/journal.pcbi.1002538
PMCID: PMC3369906  PMID: 22685391
25.  Utilization of Services in a Randomized Trial Testing Phone- and Web-Based Interventions for Smoking Cessation 
Nicotine & Tobacco Research  2011;13(5):319-327.
Introduction:
Phone counseling has become standard for behavioral smoking cessation treatment. Newer options include Web and integrated phone–Web treatment. No prior research, to our knowledge, has systematically compared the effectiveness of these three treatment modalities in a randomized trial. Understanding how utilization varies by mode, the impact of utilization on outcomes, and predictors of utilization across each mode could lead to improved treatments.
Methods:
One thousand two hundred and two participants were randomized to phone, Web, or combined phone–Web cessation treatment. Services varied by modality and were tracked using automated systems. All participants received 12 weeks of varenicline, printed guides, an orientation call, and access to a phone supportline. Self-report data were collected at baseline and 6-month follow-up.
Results:
Overall, participants utilized phone services more often than the Web-based services. Among treatment groups with Web access, a significant proportion logged in only once (37% phone–Web, 41% Web), and those in the phone–Web group logged in less often than those in the Web group (mean = 2.4 vs. 3.7, p = .0001). Use of the phone also was correlated with increased use of the Web. In multivariate analyses, greater use of the phone- or Web-based services was associated with higher cessation rates. Finally, older age and the belief that certain treatments could improve success were consistent predictors of greater utilization across groups. Other predictors varied by treatment group.
Conclusions:
Opportunities for enhancing treatment utilization exist, particularly for Web-based programs. Increasing utilization more broadly could result in better overall treatment effectiveness for all intervention modalities.
doi:10.1093/ntr/ntq257
PMCID: PMC3082503  PMID: 21330267

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