Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort

Background: Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.
Methods: We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18th August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per standard deviation increase).
Results: There were 421,469 eligible participants, 1,649 confirmed infections, 968 COVID-19-related hospitalisations, and 444 COVID-19-related deaths. Compared to never smokers, current smokers had higher risks of hospitalisation (odds ratio [OR] 1.80 [95% CI: 1.26-2.29]) and mortality (smoking 1-9/day: OR 2.14 [95% CI: 0.87-5.24]; 10-19/day: OR 5.91 [95% CI: 3.66-9.54]; 20+/day: OR 6.11 [95% CI 3.59-10.42]). In MR analyses of 281,105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45 [95% CI: 1.10-1.91]) and hospitalisation (OR 1.60 [95% CI: 1.13-2.27]). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51 [95% CI: 1.20-5.24]; hospitalisation OR 5.08 [95% CI: 2.04-12.66] and death 10.02 [95% CI: 2.53-39.72]).
Interpretation: Congruent results from two analytical approaches support a causal effect of tobacco smoking on risk of severe COVID-19.