Low-density lipoprotein cholesterol and risk of COPD: a Mendelian randomization study

Statins have shown effects on exacerbation rates and lung function in individuals with chronic obstructive pulmonary disease (COPD) in randomized controlled trials. This has led to speculation that elevated LDL cholesterol may increase the risk of adverse COPD outcomes. We tested the hypothesis that high LDL cholesterol is causally associated with increased risk of severe COPD exacerbation, COPD-specific mortality, and spirometric COPD through a one-sample Mendelian randomization study design using individual-level data in two cohorts. We examined 108,438 adults from the Copenhagen General Population Study (CGPS). A weighted allele score was calculated using nine biologically relevant genetic variants associated with LDL cholesterol levels, and causal risk estimates for the three outcomes were determined using instrumental variable analysis. Findings were validated using one-sample Mendelian randomization in 389,627 individuals from the UK Biobank (UKB). Causal odds ratios from the CGPS were not statistically significant for severe COPD exacerbation (odds ratio (OR) 1.12 (95% CI: 0.88–1.42), p = 0.34) or COPD-specific mortality (OR 1.08 (0.69–1.69), p = 0.74). Similar findings were seen in the UKB. Causal estimates showed a decreased risk of cross-sectional spirometric COPD with 1 mmol/L (39 mg/dL) higher LDL cholesterol in the CGPS (OR 0.78 (0.66–0.92), p < 0.001); however, causal estimates were not statistically significant in the UKB (OR 1.03 (0.95–1.11), p = 0.50). Sensitivity analyses using MR Egger, inverse-variance weighted, weighted median, and weighted mode methods did not indicate a true causal association for any outcome in either cohort. In conclusion, in the CGPS and UKB, high LDL cholesterol did not causally increase the risk of severe COPD exacerbation and COPD-specific mortality. Further, our findings do not provide consistent evidence to support a causal role of high LDL cholesterol in reducing the risk of developing COPD.