Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study

This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. Methods Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. Findings Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). Interpretation Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.
Source: Thorax - Category: Respiratory Medicine Authors: Tags: Thorax Interstitial lung disease Source Type: research