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Original research
Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study
  1. Junfeng Huang1,2,
  2. Zikai Lin1,2,
  3. Jinsheng Lin1,2,
  4. Shuojia Xie1,2,
  5. Shixin Xia1,2,
  6. Gengjia Chen1,2,
  7. Ziwen Zheng1,2,
  8. Zhe Xu1,2,
  9. Fangcheng Liu1,2,
  10. Hongkai Wu1,
  11. Shiyue Li1,2
  1. 1 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
  2. 2 Guangzhou Medical University, Guangzhou, Guangdong, China
  1. Correspondence to Shiyue Li, Respiratory Medicine, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China; lishiyue{at}188.com

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.

  • Pulmonary alveolar proteinosis

Data availability statement

Data are available in a public, open access repository. The summary statistics of aPAP are deposited at the National Bioscience Database Center (NBDC) Human Database with the accession code hum0197.v2. The expression quantitative trait loci summary-level data were obtained from eQTLGen Consortium (https://www.eqtlgen.org/) or GTEx Consortium V8 (https://gtexportal.org/). The datasets are publicly available without permission or confirmation for their reuse. Detailed information for these datasets is summarised in online supplemental table S1. Clinical data are available upon reasonable request.

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Data availability statement

Data are available in a public, open access repository. The summary statistics of aPAP are deposited at the National Bioscience Database Center (NBDC) Human Database with the accession code hum0197.v2. The expression quantitative trait loci summary-level data were obtained from eQTLGen Consortium (https://www.eqtlgen.org/) or GTEx Consortium V8 (https://gtexportal.org/). The datasets are publicly available without permission or confirmation for their reuse. Detailed information for these datasets is summarised in online supplemental table S1. Clinical data are available upon reasonable request.

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Footnotes

  • HW and SL are joint senior authors.

  • JH, ZL, JL and SX contributed equally.

  • Contributors Conceptualisation: JH, HW and SL. Data curation: JL, SXia, GC, ZZ, ZX and FL. Formal analysis: JH, ZL, JL and SXie. Funding acquisition: SL. Investigation: SXia, GC, ZZ, ZX and FL. Methodology: JH, ZL and SXie. Project administration: HW and SL. Resources: JH and JL. Software: ZL, SXie and SXia. Supervision: HW and SL. Validation: JH, ZL and SXie. Visualisation: JH, ZL, JL and SXie. Writing—original draft: ZL and JL. Writing—review and editing: JH, HW and SL. Guarantor: SL.

  • Funding This work was supported by the Innovation team of respiratory diseases and regenerative medicine (2021KCXTD028), Zhongnanshan Medical Foundation of Guangdong province (ZNSA-2020013) and the Guangzhou clinical high-tech project (2023C-GX04). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. All authors had full access to all of the study data and shared responsibility for the decision to submit for publication.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.