Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies. Although we know that smoking tobacco negatively impacts health, we know relatively little about whether nicotine plays a role in causing poor health outcomes. When used for short periods of time, nicotine appears to have little impact on health. However, until recently, nicotine has rarely been used for long periods without accompanying exposure to tobacco smoke, so it is hard to disentangle the effects of regular nicotine use from the effects of tobacco smoke exposure. In this study, we aimed to dissect the effects of nicotine versus non-nicotine constituents of tobacco smoke on heart and lung health using multivariable Mendelian randomisation and data from a range of sources (including UK Biobank). We found that nicotine does not appear to be an independent cause of poor lung function, lung cancer, chronic obstructive pulmonary disease, or coronary heart disease, but does increase heart rate. These results support previous evidence which suggests that nicotine on its own does not directly cause poor health outcomes, with the exception of increasing heart rate.