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

Zikai Lin, Shuojia Xie, Zhe Xu, Junfeng Huang, Gengjia Chen, Ziwen Zheng, Shiyue Li, Hongkai Wu, Jinsheng Lin, Shixin Xia, Fangcheng Liu

Journal: Thorax 2024;79(2):135-143

PMID: 38124156

Full Text on HighWire View on PubMed

Abstract

BACKGROUND

Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. 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.

Address: Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.; Guangzhou Medical University, Guangzhou, Guangdong, China.; Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.; Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China [email protected].; Guangzhou Medical University, Guangzhou, Guangdong, China.

DOI: 10.1136/thorax-2023-220789

Link outs

Free resources

Miscellaneous:

https://assays.cancer.gov/non-CPTAC-3369

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-ASAP1-1

Subscription / membership required

Full Text Sources:

MeSH Terms: Humans, Cholesterol, HDL, Cholesterol, LDL, Genetic Predisposition to Disease, Genome-Wide Association Study, Lipid Metabolism, Proprotein Convertase 9, Pulmonary Alveolar Proteinosis, Mendelian Randomization Analysis