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Introduction: Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin.Methods: We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption.Results: In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers.Conclusion: Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal.Implications: Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3-known to influence individual tobacco consumption-as instrumental variable for tobacco consumption.Methods: Data from 90 108 participants in the Copenhagen General Population Study was used. Exposures included self-reported cigarettes/day and pack years and the CHRNA3 rs1051730 genotype as instrumental variable for tobacco consumption. Three dimensions of psychological distress were studied: Stress, fatigue, and hopelessness. Analyses with the CHRNA3 genotype were stratified by smoking status.Results: Self-reported amount of smoking was associated with all three dimensions of psychological distress. For instance among participants smoking 30 cigarettes/day or more, the odds ratio (OR) for stress was 1.67 (95% confidence interval [CI] 1.47-1.89) compared to never-smokers. Corresponding ORs for fatigue and hopelessness were 2.18 (95% CI 1.92-2.47) and 3.08 (95% CI 2.62-3.62). Among current smokers, homozygotes and heterozygotes for the CHRNA3 genotype had higher tobacco consumption than noncarriers. Nevertheless, the CHRNA3 genotype was not associated with psychological distress neither in current nor in former or never-smokers. For instance among current smokers, the OR for stress was 1.02 (95% CI 0.91-1.15) among homozygotes compared to noncarriers of the CHRNA3 genotype.Conclusions: Though a strong association between tobacco consumption and psychological distress was found, there was no clear evidence that high tobacco consumption was causally related to psychological distress.Implications: Smoking is associated with several mental health outcomes and smoking cessation is associated with improved mental health. Causality in the association between smoking and mental health is difficult to establish using observational data. Using a genotype known to influence tobacco consumption as instrumental variable for amount of smoking, we found no clear evidence of a direct causal path between high tobacco consumption and psychological distress. Whatever causes the strong association between tobacco consumption and psychological distress, the co-occurrence is important to consider both in interventions for smoking prevention and cessation. [ABSTRACT FROM AUTHOR]