Association of smoking, lung function and COPD in COVID‐19 risk: a two‐step Mendelian randomization study

Abstract

Background and Aims Smoking increases the risk of severe COVID‐19, but whether lung function or chronic obstructive pulmonary disease (COPD) mediate the underlying associations is unclear. We conducted the largest Mendelian randomization study to date, to our knowledge, to address these questions. Design Mendelian randomization study using summary statistics from genome‐wide association studies (GWAS), FinnGen and UK Biobank. The main analysis was the inverse variance weighted method, and we included a range of sensitivity analyses to assess the robustness of the findings. Setting GWAS which included international consortia, FinnGen and UK Biobank. Participants The sample size ranged from 193 638 to 2 586 691. Measurements Genetic determinants of life‐time smoking index, lung function [e.g. forced expiratory volume in 1 sec (FEV 1 )], chronic obstructive pulmonary disease (COPD) and different severities of COID‐19. Results Smoking increased the risk of COVID‐19 compared with population controls for overall COVID‐19 [odds ratio (OR) = 1.19 per standard deviation (SD) of life‐time smoking index, 95% confidence interval (CI) = 1.11–1.27], hospitalized COVID‐19 (OR = 1.67, 95% CI = 1.42–1.97) or severe COVID‐19 (OR = 1.48, 95% CI = 1.10–1.98), with directionally consistent effects from sensitivity analyses. Lung function and COPD liability did not appear to mediate these associations. Conclusion There is genetic evidence that smoking probably increases the risk of severe COVID‐19 and possibly also milder forms of COVID‐19. Decreased lung function and increased risk of chronic obstructive pulmonary disease do not seem to mediate the effect of smoking on COVID‐19 risk.

The way forward to achieve high COVID-19 vaccination and revaccination coverage in a city amid a period of tranquility

“…Smoking status was associated with the COVID vaccination intention in this study, unlike in our previous study. Taking off their protective mask for smoking ( 23 ) and the increased infection risk attributed to smoking ( 24 ) may explain why smokers were more likely to receive a booster dose than non-smokers. To escape from the restrictions imposed by the vaccine bubble policies for unvaccinated individuals, smokers, who are usually lower in health awareness ( 25 ), might tend to disregard the risk of potential adverse effects of the booster and could be more motivated to take the booster.…”

Potential Bias in Assessing the Tobacco/Nicotine—COVID-19 Association—How to Improve Our Level of Understanding

“…This can be assessed by a mediational analysis. For example, Au Yeung et al [ 5 ] have shown in a Mendelian randomization study that the smoking–hospitalization for and the severity of COVID-19 relationships do not involve the mediation effect of lung function or chronic obstructive pulmonary disease, lending support to the hypothesis that these two outcomes are specifically associated with smoking.…”

“…Results for the risk of hospitalization and death rate were similar by using the two different approaches. Clift et al’s [ 12 ] Mendelian randomization data were later confirmed by Au Yeung et al [ 5 ] using the lifetime smoking index [ 13 ].…”

“…According to currently available data, the role of smoking, tobacco, or other nicotine inhalation delivery systems’ use in acquiring SARS-CoV-2 infections is not established. In contrast, the harmful effect of tobacco smoking on the severity and mortality of COVID-19 is well-established [ 5 , 12 , 15 , 16 , 17 , 18 , 19 ]. This means that current regulatory strategies [ 20 ] to fight the tobacco epidemic should not be changed.…”

Commentary: Smoking, nicotine and COVID-19 outcomes: unprecedented challenges to epidemiologists

“… 1 However, in another recent Mendelian randomization study using summary statistics from genome-wide association studies (GWAS), FinnGen and UK Biobank showed ‘genetic evidence that smoking probably increases the risk of severe COVID-19 and possibly also milder forms of COVID-19’. 5 Moreover, a meta-analysis found six Mendelian randomization studies which consistently demonstrated ‘strong associations of smoking traits, including smoking initiation, smoking heaviness and lifetime smoking index (which combined smoking initiation, duration, heaviness and cessation), in the risk of COVID-19 severity, hospitalzation and mortality’, and the authors suggested that the mechanism may be ‘an increased expression of ACE2, a receptor for SARS-CoV-2 in the airway epithelium’ in smokers. 6 …”