Proteome-wide Mendelian randomization identifies causal plasma proteins in Interstitial lung disease

Abstract Background Interstitial lung disease (ILD) has exhibited limited overall treatment advancements, with scant exploration into circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). Therefore, our study aims to investigate potential drug targets and circulating protein biomarkers for ILD and its subtypes. Methods 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, bidirectional Mendelian randomization analysis, and phenotype scanning. Results Genetic prediction levels of eight proteins were associated with the risk of ILD or its subtypes. Through a series of sensitivity analyses, three proteins were identified as priority proteins for circulating biomarkers and potential therapeutic targets. Specifically, CDH15(Cadherin-15)increased the risk of ILD༈OR = 1.32, 95%CI 1.16–1.49, P = 1.60×10 − 6 ༉, and LTBR༈Lymphotoxin-beta receptor༉increased the risk of sarcoidosis༈OR = 1.39, 95%CI 1.20–1.61, p = 9.38×10 − 6 ༉, while ADAM15 (A disintegrin and metalloproteinase 15) were protective proteins for ILD༈OR = 0.86, 95% CI 0.81–0.92, P = 1.59×10 − 6 ༉and IPF༈OR = 0.81, 95% CI 0.75–0.89). Moreover, no causal proteins for other ILD subtypes were found. Conclusion This study identified several new circulating protein biomarkers associated with the risk of ILD and its subtypes. It offers a new perspective for future research on the diagnosis and treatment of ILD and its subtypes.