The impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bi-directional Mendelian randomization study

Background Observational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be susceptible to residual confounding. We conducted a 2 sample Mendelian randomization study using summary statistics from genome wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function. Methods We obtained genetic instruments for forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) from publicly available UK Biobank summary statistics (n = 421,986). We applied these genetic instruments for FEV 1 (260) and FVC (320) to publicly available GWAS summary statistics for coronary artery disease (CAD) (n = 184,305), stroke and its subtypes (n = 446,696), atrial fibrillation (n = 1,030,836), and heart failure (n = 977,320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, and multivariable Mendelian randomization. We also conducted bi-directional Mendelian randomization to assess whether CVD affects lung function. Results FEV 1 and FVC were inversely associated with CAD (odds ratio (OR) per standard deviation (SD) increase, 0.72 (95% confidence interval (CI) 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (0.82 to 1.00)), ischemic stroke (0.87 (95%CI 0.77 to 0.99), 0.90 (95%CI 0.80 to 1.00)), small vessel stroke (0.78, (95%CI 0.61 to 1.00), 0.74 (95%CI 0.61 to 0.92)), and large artery stroke (0.69 (95%CI 0.54 to 0.89), 0.72 (95%CI 0.57 to 0.91)). FEV 1 and FVC were inversely associated with type 2 diabetes (0.75 (95%CI 0.62 to 0.90), 0.67 (95%CI 0.58 to 0.79)) and systolic blood pressure. Sensitivity analyses produced similar direction for most outcomes although the magnitude sometimes differed. Adjusting for height attenuated results for CAD (e.g. OR for 1SD FEV 1 0.95 (0.76 to 1.20), but this may reflect weak instrument bias. This adjustment did not attenuate effects for stroke or type 2 diabetes. No strong evidence was observed for CVD affecting lung function. Conclusion Higher lung function likely protect against CAD and stroke.