Variation in the gene coding for the M5 muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction : evidence from a prospective population based cohort study of young adults

Background: The mesolimbic structures of the brain are important in the anticipation and perception of reward. Moreover, many drugs of addiction elicit their response in these structures. The M5 muscarinic receptor (M5R) is expressed in dopamine-containing neurones of the substantia nigra pars compacta and ventral tegmental area, and regulates the release of mesolimbic dopamine. Mice lacking M5R show a substantial reduction in both reward and withdrawal responses to morphine and cocaine. The CHRM5, the gene that codes for the M5R, is a strong biological candidate for a role in human addiction. We screened the coding and core promoter sequences of CHRM5 using denaturing high performance liquid chromatography to identify common polymorphisms. Additional polymorphisms within the coding and core promoter regions that were identified through dbSNP were validated in the test population. We investigated whether these polymorphisms influence substance dependence and dose in a cohort of 1947 young Australians.

Results: Analysis was performed on 815 participants of European ancestry who were interviewed at wave 8 of the cohort study and provided DNA. We observed a 26.8% increase in cigarette consumption in carriers of the rs7162140 T-allele, equating to 20.1 cigarettes per week (p=0.01). Carriers of the rs7162140 T-allele were also found to have nearly a 3-fold increased risk of developing cannabis dependence (OR=2.9 (95%CI 1.1-7.4); p=0.03).

Conclusion: Our data suggest that variation within the CHRM5 locus may play an important role in tobacco and cannabis but not alcohol addiction in European ancestry populations. This is the first study to show an association between CHRM5 and substance use in humans. These data support the further investigation of this gene as a risk factor in substance use and dependence.

Association of adolescent symptoms of depression and anxiety with daily smoking and nicotine dependence in young adulthood : findings from a 10-year longitudinal study

Aims To examine the association of adolescent depression and anxiety symptoms with daily smoking and nicotine dependence in young adulthood.

Design A prospective cohort study of adolescent and young adult health (n = 1943). Teen assessments occurred at 6-monthly intervals, with two follow-up assessments in young adulthood (wave 7, 1998; wave 8, 2001–03).

Setting Victoria, Australia.

Participants Students who participated at least once during the first six (adolescent) waves of the cohort study.

Measurements Adolescent depression and anxiety symptomswere assessed using the Revised Clinical Interview Schedule (CIS-R).Young adult tobacco usewas defined as: daily use (6 or 7 days perweek) and dependent use (>4 on the Fagerstrom Test for Nicotine Dependence).

Findings Among adolescent ‘less than daily’ smokers, those with high levels of depression and anxiety symptoms had an increased risk of reporting nicotine dependence in young adulthood [odds ratio (OR) 3.3, 95% confidence interval (CI) 1.2–9.1] compared to young adults who had low levels of adolescent depression and anxiety symptoms, after adjusting for potential confounding factors. Similarly, in the adjusted model (OR 1.9, 95% CI 1.0–3.4), among adolescent ‘daily’ smokers, those with high levels of depression and anxiety symptoms had an almost two-fold increase in the odds of reporting nicotine dependence in young adulthood compared to young adults with low levels of adolescent depression and anxiety symptoms.

Conclusions Adolescent smokerswith depression and anxiety symptoms are at increased risk for nicotine dependence into young adulthood. They warrant vigilance from primary care providers in relation to tobacco use well into adulthood.

Age at quitting smoking as a predictor of risk of cardiovascular disease incidence independent of smoking status, time since quitting and pack-years

Background: Risk prediction for CVD events has been shown to vary according to current smoking status, pack-years smoked over a lifetime, time since quitting and age at quitting. The latter two are closely and inversely related. It is not known whether the age at which one quits smoking is an additional important predictor of CVD events. The aim of this study was to determine whether the risk of CVD events varied according to age at quitting after taking into account current smoking status, lifetime pack-years smoked and time since quitting.
Findings. We used the Cox proportional hazards model to evaluate the risk of developing a first CVD event for a cohort of participants in the Framingham Offspring Heart Study who attended the fourth examination between ages 30 and 74 years and were free of CVD. Those who quit before the median age of 37 years had a risk of CVD incidence similar to those who were never smokers. The incorporation of age at quitting in the smoking variable resulted in better prediction than the model which had a simple current smoker/non-smoker measure and the one that incorporated both time since quitting and pack-years. These models demonstrated good discrimination, calibration and global fit. The risk among those quitting more than 5 years prior to the baseline exam and those whose age at quitting was prior to 44 years was similar to the risk among never smokers. However, the risk among those quitting less than 5 years prior to the baseline exam and those who continued to smoke until 44 years of age (or beyond) was two and a half times higher than that of never smokers.
Conclusions: Age at quitting improves the prediction of risk of CVD incidence even after other smoking measures are taken into account. The clinical benefit of adding age at quitting to the model with other smoking measures may be greater than the associated costs. Thus, age at quitting should be considered in addition to smoking status, time since quitting and pack-years when counselling individuals about their cardiovascular risk.

Framingham risk prediction equations for incidence of cardiovascular disease using detailed measures for smoking

Current prediction models for risk of cardiovascular disease (CVD) incidence incorporate smoking as a dichotomous yes/no measure. However, the risk of CVD associated with smoking also varies with the intensity and duration of smoking and there is a strong association between time since quitting and the risk of disease onset. This study aims to develop improved risk prediction equations for CVD incidence incorporating intensity and duration of smoking and time since quitting. The risk of developing a first CVD event was evaluated using a Cox’s model for participants in the Framingham offspring cohort who attended the fourth examination (1988–92) between the ages of 30 and 74 years and were free of CVD (n=3751). The full models based on the smoking variables and other risk factors, and reduced models based on the smoking variables and non-laboratory risk factors demonstrated good discrimination, calibration and global fit. The incorporation of both time since quitting among past smokers and pack-years among current smokers resulted in better predictive performance as compared to a dichotomous current/non-smoker measure and a current/quitter/never smoker measure. Compared to never smokers, the risk of CVD incidence increased with pack-years. Risk among those quitting more than five years prior to the baseline exam and within five years prior to the baseline exam were similar and twice as high as that of never smokers. A CVD risk equation incorporating the effects of pack-years and time since quitting provides an improved tool to quantify risk and guide preventive care.

Smokers and ex-smokers reaction to anti-smoking advertising : a mixed methods approach

Anti-smoking advertising is a central component of modern public health policy. Nevertheless, some smokers have reported that viewing anti-smoking advertising provokes intense nicotine craving. Anti-smoking advertising frequently features images of cigarettes and of individuals smoking. However, research indicates that images of tobacco paraphernalia may induce cravings in individuals addicted to nicotine. The effects of the presence of smoking cues in anti-smoking advertising were considered in the present study. Smokers and ex-smokers (N=63) were randomly assigned to view an anti-smoking advertisement or to complete a control task. Urge to smoke was measured pre- and post-test. Qualitative responses to anti-smoking advertising were also elicited from all participants in the intervention groups. According to both qualitative and quantitative data analyses viewing anti-smoking advertising, even with images of smoking related paraphernalia, led to decreases in craving amongst smokers. Ex-smokers experienced no change in quantitatively measured craving after viewing anti-smoking advertising. These findings are inconsistent with findings from studies using neutral or positive smoking cues. Qualitative data shows that no smokers or ex-smokers who viewed anti-smoking advertising reported an increase in tobacco craving as a result of viewing the campaign. Implications of these findings for future research and anti-smoking campaigns are discussed.

Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine

Defective efferocytosis may perpetuate inflammation in smokers with or without chronic obstructive pulmonary disease (COPD). Macrophages may phenotypically polarize to classically activated M1 (proinflammatory; regulation of antigen presentation) or alternatively activated M2 (poor antigen presentation; improved efferocytosis) markers. In bronchoalveolar lavage (BAL)–derived macrophages from control subjects and smoker/ex-smoker COPD subjects, we investigated M1 markers (antigen-presenting major histocompatibility complex [MHC] Classes I and II), complement receptors (CRs), the high-affinity Fc receptor involved with immunoglobulin binding for phagocytosis (Fc-gamma receptor, FcγR1), M2 markers (dendritic cell–specific intercellular adhesion molecule-grabbing nonintegrin [DC-SIGN] and arginase), and macrophage function (efferocytosis and proinflammatory cytokine production in response to LPS). The availability of glutathione (GSH) in BAL was assessed, because GSH is essential for both M1 function and efferocytosis. We used a murine model to investigate macrophage phenotype/function further in response to cigarette smoke. In lung tissue (disaggregated) and BAL, we investigated CRs, the available GSH, arginase, and efferocytosis. We further investigated the therapeutic effects of an oral administration of a GSH precursor, cysteine l-2-oxothiazolidine-4-carboxylic acid (procysteine). Significantly decreased efferocytosis, available GSH, and M1 antigen–presenting molecules were evident in both COPD groups, with increased DC-SIGN and production of proinflammatory cytokines. Increased CR-3 was evident in the current-smoker COPD group. In smoke-exposed mice, we found decreased efferocytosis (BAL and tissue) and available GSH, and increased arginase, CR-3, and CR-4. Treatment with procysteine significantly increased GSH, efferocytosis (BAL: control group, 26.2%; smoke-exposed group, 17.66%; procysteine + smoke-exposed group, 27.8%; tissue: control group, 35.9%; smoke-exposed group, 21.6%; procysteine + smoke-exposed group, 34.5%), and decreased CR-4 in lung tissue. Macrophages in COPD are of a mixed phenotype and function. The increased efferocytosis and availability of GSH in response to procysteine indicates that this treatment may be useful as adjunct therapy for improving macrophage function in COPD and in susceptible smokers.

Emerging nutritional and lifestyle risk factors for bone health in young women: a mixed longitudinal twin study

Late adolescence and early adulthood are times of major behavioral transition in young women as they become more independent and make choices about lifestyle that will affect their long-term health. We prospectively evaluated nutritional and lifestyle factors in 566 15 30-year-old female twins participating in a mixed longitudinal study of diet and lifestyle.Twins completed 790 visits including questionnaires and measures of anthropometry. Nonparametric tests (chi-square, Mann-Whitney U, and Kruskal-Wallis; SPSS) were used to examine age-related differences in selected variables. Dietary calcium intake by short food frequency questionnaire was relatively low [511 (321,747)] mg/day (median, IQR; 60 % of estimated daily total) and did not vary significantly with age. The number of young women who reported ever consuming alcohol (12+ standard drinks ever) increased from 50 % under 18 years to 93 99 % for the 18+ age groups. Of those who consumed alcohol in the preceding year, monthly intake doubled from under 18 years (5.7, 3.9, 19.0 standard drinks; median, IQR) to 18+ years (12.0, 4.7, 26.0; P < 0.001) with the highest consumers being 21 23 and 27 29 years. At age 15 17 years, 14 % reported ever smoking and by age 27–29, 51 % had smoked (P = 0.002). Under the age of 20 years, average cigarette consumption in smokers was six cigarettes per day, increasing to ten above age 20 (P < 0.001). Participation in sporting activity decreased with age (P < 0.001): 47.5 % of 15–17-year-olds undertook 4 or more hour/week of sport, compared with 23.5 % at age 27–29 years. Conversely, sedentary behavior increased with age: 25.0 % of 15–17-year-olds reported 1 or less hour/week of exercise compared with 50.0 % at age 27–29 years. BMI increased with age (P = 0.011), from 21.3 (19.5, 23.6; median, IQR) in the youngest to 23.1 (21.5, 25.9) in the oldest. These highly significant changes in behavior in young women as they transitioned into independent adult living are predicted to impact adversely on bone and other health outcomes in later life. It is crucial to improve understanding of the determinants of these changes and to develop effective interventions to improve long-term health outcomes in young women.