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Background Compared to white smokers, Black smokers are at disproportionately higher risk for smoking-related disease, despite consuming fewer cigarettes per day (CPD). To examine racial disparities in biobehavioral influences on smoking and disease risk, we analyzed the relationship between self-reported tobacco dependence and intensity of tobacco smoke exposure per cigarette, on the one hand, and intensity of nicotine intake per cigarette, on the other. Methods In 270 Black and 516 white smokers, smoke exposure was measured by expired carbon monoxide (CO), and nicotine intake was measured by plasma cotinine (COT) and cotinine+3′-hydroxycotinine ([COT + 3HC]). Using linear regression analyses, we analyzed how the Fagerstrom Test for Cigarette Dependence (FTCD) predicted intensity of smoke exposure per cigarette (CO/CPD) and intensity of nicotine intake per cigarette (COT/CPD; [COT + 3HC]/CPD), and how race moderated these relations. Results Overall, Black smokers consumed fewer CPD than white smokers and had higher levels of CO/CPD, COT/CPD, and [COT + 3HC]/CPD. These elevations were most pronounced at lower levels of dependence: amongst Black smokers, FTCD negatively predicted intensity of smoke exposure as measured by CO/CPD (B = −0.12, 95% CI = −0.18, −0.05, p = 0.0003) and intensity of nicotine intake as measured by [COT + 3HC]/CPD (B = −1.31, 95% CI = −2.15, −0.46, p = 0.002). Conclusions Low-dependence Black smokers had higher intensities of both smoke exposure and nicotine intake per cigarette compared to similarly dependent white smokers, suggesting that measures of dependence, exposure, and intake underestimate incremental risk of each cigarette to Black smokers.

Objective Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. Method In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. Results For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2 = 8.15, df = 2, omnibus-p = 0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald = 3.94, df = 1, p = 0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Conclusions Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.

This study tests whether the genetic predictor (CHRNA5 nicotine receptor gene variants) and an environmental risk factor (partner smoking) interact in the prediction of smoking reduction.Subjects were from a community-based, longitudinal study of women (n=1856) who smoked before pregnancy, and a randomized comparative effectiveness smoking cessation trial (n=1065). Smoking reduction was defined as the trajectory of self-reported smoking quantities over time in the observational study, and as the trajectory of alveolar CO levels in the cessation trial.In the pregnancy study, rs16969968 genotype and partner smoking status interacted such that the smoking reduction was lowest for expectant mothers with high genetic risk and partner smoking, and highest for those with high genetic risk but not partner smoking (interaction of genotype×partner smoking on smoking quantity trajectory slope β=0.071, 95%CI=0.013, 0.13, p=0.017). In the clinical trial, a similar interaction was found (interaction β=0.20, 95%CI=0.049, 0.36, p=0.010). Furthermore, these associations were moderated by pharmacotherapy such that the interactive relation of genetic and environmental factors occurred in the placebo group, but not in the active pharmacotherapy group (interaction of genotype×partner smoking×pharmacotherapy on CO trajectory slope β=-0.25, 95%CI=-0.42, -0.091, p=0.0023).The CHRNA5 genetic risk synergized the effect of partner smoking, producing an especially low likelihood of successful smoking reduction in two complementary studies. This suggests that the genetic vulnerability may be mitigated by altering environmental factors. In addition, cessation pharmacotherapy neutralizes the increase in cessation failure associated with combined genetic and environmental risks, which has possible relevance to treatment algorithms.

a b s t r a c t Background: The associations between nicotine dependence and specific variants in the nicotinic receptor CHRNA5-A3-B4 subunit genes are irrefutable with replications in many studies. The relationship between the newly identified genetic risk variants for nicotine dependence and comorbid psychiatric disorders is unclear. We examined whether these genetic variants were associated with comorbid disorders and whether comorbid psychiatric disorders modified the genetic risk of nicotine dependence. Methods: In a case control study of nicotine dependence with 2032 subjects of European descent, we used logistic regression models to examine the pleiotropy and risk moderation. Comorbid disorders examined were alcohol dependence, cannabis dependence, major depressive disorder, panic attack, social phobia, posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), conduct disorder, and antisocial personality disorder (ASPD). Results: Nicotine dependence was associated with every examined comorbid psychiatric disorders, with odds ratio varying from 1.75 to 3.33. No evidence supported the associations between the genetic variants and the comorbid disorders (pleiotropy). No evidence suggested that the risks for nicotine dependence associated with the genetic variants vary with comorbid psychiatric disorders in general, but the power was limited in detecting interactions. Conclusions: The genetic risks of nicotine dependence associated with the CHRNA5-A3-B4 subunit genes are specific, and not shared among commonly comorbid psychiatric disorders. The risks for nicotine dependence associated with these genetic variants are not modified by comorbid psychiatric disorders such as major depressive disorder or alcohol dependence. However, the power is an important limitation in studying the interplay of comorbidity and genetic variants.