FKBP5 is a Biomarker for Idiopathic Pulmonary Fibrosis based on a Multi-omic Study Integrating xQTLs.

INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is associated with poor prognosis.

METHODS From related methylation, expression, and protein quantitative trait loci investigations (eQTL, mQTL, and pQTL), summary-level data were extracted. We obtained Genome-wide association study (GWAS) summary statistics of IPF from the Allen's study (discovery), the FinnGen study (finngen_R10_IPF) (replication), and the GWAS catalog study (replication). Summary-data based Mendelian randomization (SMR) and colocalization analysis were utilized to evaluate the relationships between gene molecular characteristics and IPF. Bioinformatics analysis was employed to validate the above results. Molecular docking and druggable targets exploration were utilized to examine the druggability of selected targets.

RESULTS After multi-omics SMR analysis and colocalization analysis, we identified six potential targets for IPF, namely RHPN1, USP28, ADAM15, FKBP5, MAD1L1, and FBXL16. By assessing relationships of the gene expression with IPF in lung tissues, specifically ADAM15 and FKBP5 were validated. Then, FKBP5 was further verified by employing bioinformatics analysis, which indicates FKBP5 may represent the most promising therapeutic target for IPF identified to date. Lastly, we identified 11 drugs that interact with FKBP5 and conducted molecular docking analyses of the top four candidate drugs with FKBP5, demonstrating favorable binding interactions.

DISCUSSION With the use of multi-omic analysis, we determined that RHPN1, USP28, ADAM15, FKBP5, MAD1L1, and FBXL16 were associated with IPF.

CONCLUSION These findings provided evidence for the feasibility of developing therapeutic targets for IPF.