A multivariable Mendelian randomisation study exploring the direct effects of nicotine on health compared with the other constituents of tobacco smoke: Implications for e-cigarette use

Objectives Given the popularity of e-cigarettes, and the lack of longitudinal evidence regarding their safety, novel methods are required to explore potential health effects resulting directly from nicotine use. The aim of this study was to explore the direct effects of nicotine compared with the other constituents of tobacco smoke on health outcomes associated with smoking. Design Observational study, using Mendelian randomisation and multivariable Mendelian randomisation analyses of summary data. Setting Summary data from two previous genome-wide association studies, and summary data generated from UK Biobank, a prospective cohort study. Participants N = 337,010 individuals enrolled in UK Biobank, and a total of N = 341,882 individuals from two previous genome-wide association studies. Main outcome measures We explored the effect of cotinine levels (as a proxy for nicotine exposure) and smoking heaviness (to capture cigarette smoke exposure) on body mass index (BMI), chronic obstructive pulmonary disease (COPD), forced vital capacity (FVC), forced expiratory volume (FEV-1), coronary heart disease (CHD), and heart rate. Results In multivariable Mendelian randomisation analyses, there was weak evidence to suggest that increased cotinine levels may cause increased heart rate among current smokers (β = 0.50 bpm, 95% CI -0.06 to 1.05). There was stronger evidence to suggest that increased smoking heaviness causes decreased BMI among current smokers (β = -1.81 kg/m2, 95% CI -2.64 to -0.98), as well as increased risk of COPD, decreased FEV-1 and FVC, and increased heart rate among ever and current smokers. We also found evidence to suggest that increased smoking heaviness causes increased risk of CHD among ever smokers. Conclusions Our combined findings are consistent with smoking-related health outcomes being caused by exposure to the non-nicotine components of tobacco smoke.