Publication date: Aug 23, 2024

Smoking behaviors, physical activities, and pulmonary diseases have been revealed to be associated with COVID-19 severity through observational research. The possible causative effect remains undetermined. To investigate this, we thus carried out a Mendelian randomization (MR) analysis. We chose genetic variants from genome-wide association studies that are strongly linked to 5 exposures related to smoking, 1 exposure related to drinking, 3 levels of physical activity, and 3 pulmonary diseases. The COVID-19 Host Genetics Initiative provided summary-level data for severe COVID-19 (13,769 cases and 1,072,442 noncases), hospitalized COVID-19 (32,519 cases and 2,062,805 noncases), and COVID-19 susceptibility (122,616 cases and 2,475,240 noncases). Univariate and multivariate MR analyses were carried out. Significant associations were found between severe COVID-19 and cigarette smoking per day (OR = 1. 357, 95% CI: 1. 087-1. 694), lifetime smoking index (OR = 2. 277, 95% CI: 1. 602-3. 325), and interstitial lung disease (OR = 1. 23, 95% CI: 1. 112-1. 362), hospitalized COVID-19 and lifetime smoking index (OR = 2. 199, 95% CI: 1. 738-2. 781), smoking initiation (OR = 1. 419, 95% CI: 1. 230-1. 637), and interstitial lung disease (OR = 1. 146, 95% CI: 1. 082-1. 214), as well as COVID-19 susceptibility and lifetime smoking index (OR = 1. 39, 95% CI: 1. 252-1. 543), smoking initiation (OR = 1. 235, 95% CI: 1. 163-1. 311), and duration of vigorous activity per day (OR = 0. 733, 95% CI: 0. 574-0. 935). Duration of vigorous activity per day was suggestively inversely linked to hospitalized COVID-19 (OR = 0. 434, 95% CI: 0. 221-0. 853) and severe COVID-19 (OR = 0. 323, 95% CI: 0. 123-0. 850). The association for lifetime smoking index remained consistent with severe COVID-19, hospitalized COVID-19, and COVID-19 susceptibility in multivariable MR analysis. Genetic liability to lifetime smoking index mediated the interstitial lung disease effects on severe COVID-19 risk (21. 0%) and hospitalized COVID-19 risk (14. 4%). This study identified several smoking behaviors, duration of vigorous activity per day, and interstitial lung disease that may be causally related to COVID-19 severity.

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Original Article