Proteome-wide mendelian randomization identifies causal plasma proteins in interstitial lung disease

Abstract

Interstitial lung disease (ILD) has shown limited treatment advancements, with minimal exploration of circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify potential drug targets and circulating protein biomarkers for ILD and its subtypes. We utilized the most recent large-scale plasma protein quantitative trait loci (pQTL) data detected from the antibody-based method and ILD and its subtypes' GWAS data from the updated FinnGen database for Mendelian randomization analysis. To enhance the reliability of causal associations, we conducted external validation and sensitivity analyses, including Bayesian colocalization and bidirectional Mendelian randomization analysis. Our study identified eight plasma proteins genetically associated with ILD or its subtypes. Among these, three proteins-CDH15 (Cadherin-15), LTBR (Lymphotoxin-beta receptor), and ADAM15 (A disintegrin and metalloproteinase 15)-emerged as priority biomarkers and potential therapeutic targets, demonstrating more reliable associations by passing a series of sensitivity analyses compared to the others. Based on these findings, we propose for the first time that CDH15, ADAM15, and LTBR hold promise as novel potential circulating protein biomarkers and therapeutic targets for the diagnosis and treatment of ILD, IPF, and sarcoidosis, respectively, especially ADAM15, and these findings have the potential to provide new perspectives for advancing the research on the heterogeneity of ILD.

Keywords: Biomarker; Drug target; Interstitial lung disease; Mendelian randomization; Protein; Subtype.

Fig. 1

Study design for identification of plasma proteins causally associated with ILD and its subtypes.

Fig. 2

Volcano plots of the MR results for proteins on the risk of (A) Sarcoidosis and (B) Interstitial lung disease. OR for increased risk of ILD and Sarcoidosis were expressed as per SD increase in plasma protein levels. The dashed horizontal black line corresponded to P = 2.64 × 10^–5 (0.05/1896). ln = natural logarithm; PVE = proportion of variance explained.

Fig. 3

External validation of the causal relationship between potential causal proteins and (A) Interstitial lung disease or (B) Sarcoidosis.

Fig. 4

Bayesian colocalization analysis of (A) ADAM15-ILD, (B) CDH15-ILD, (C) LTBR-Sarcoidosis and (D) VEGFB-Sarcoidosis. Diamond purple points represented the SNP that with the minimal sum of P value in corresponded protein GWAS and ILD or its subtypes GWAS.