A Two-Step Mendelian Randomization Involving Chronic Obstructive Pulmonary Disease, COVID-19 and Risk Factors.

Introduction and Objectives: Smoking is a risk factor for Covid-19 due to the destruction of heart and lungs from tobacco products. Increased smoking increases complications related to Covid-19, however, the association between chronic obstructive pulmonary disorder (COPD), environmental factors, and how the lung function mediates the association remains unclear. Therefore, our primary objective is to conduct a Mendelian randomization to investigate whether COPD, environmental factors and lung function has a mediating effect between smoking and the severity of COVID-19.
Methods: A two-step Mendelian randomization design was employed using genetic data from genome-wide association studies (GWAS). The instrumental variable was the genetic variants (Z) associated with smoking, COPD, lung function (forced expiratory volume per second (FEV1), and COVID-19 phenotypes (hospitalized, severe and overall covid-19) were selected. The first step involved estimating the associations between instruments and their respective phenotypes, while the second step examined the relationships between instruments and outcomes, as well as instruments and mediators. Various sensitivity analyses were conducted to assess the robustness of the findings.
Participants: A sample size ranging between 195 773 to 289 887.
Measurements: Lung function was measured per second [forced expiratory volume per second (FEV1)], genetic determinants of lifetime smoking index, and varying severities of COVID-19 and COPD.
Results: COVID-19 Severe (OR =1.48, 95% CI = 1.10 to 1.98) and COVID-19 Hospitalized (OR = 1.67, 95% CI = 1.42 to 1.97), alongside additional sensitivity analyses showed consistent directional effects. Smoking exacerbated COVID-19's risk in the experimental group more than in control populations: Odds Rations (OR) of 1.19 per standard deviation (SD), based on the lifetime smoking index, and a 95% Confidence Interval (CI) of 1.11 to 1.27. COPD and lung function did not mediate the associations.
Conclusions: There exists strong genetic evidence linking environmental factors, smoking and lung function, and COVID-19's severity. Mild COVID-19 is also captured, but to a lesser extent, through minimal evidence. Low lung function exacerbates COPD but does not mediate the implications of smoking on the risk of COVID-19. Our study has implications in the public health policy and messaging for smokers and risks of COVID-19.