Abstract:

Objective To screen the key genetic， diagnostic and therapeutic targets of chronic obstructive pulmonary disease （COPD） patients by using microarray datasets and Mendelian randomization （MR） method， and to provide the evidence for clinical diagnosis and treatment of COPD. Methods Four COPD gene expression profile datasets were obtained from the Gene Expression Omnibus （GEO） database. The data were processed and normalized using R software， and differentially expressed genes （DEGs） were screened. MR analysis was performed to explore the causal relationship between COPD and expression quantitative trait loci （eQTL）， intersection with DEGs was taken to identify potential key targets. Gene Set Enrichment Analysis （GSEA）， Gene Ontology （GO） functional enrichment analysis， and Kyoto Encyclopedia of Genes and Genomes （KEGG） signaling pathway enrichment analysis were conducted to investigate the functional roles and pathways of the key targets， external datasets were used to validate their expression. Results A total of 1 571 DEGs were screened， including 820 upregulated genes and 751 downregulated genes. MR analysis identified 286 COPD-related genes， and intersection with DEGs revealed 3 upregulated genes： diacylglycerol kinase gamma （DGKG）， neurofilament heavy polypeptide （NEFH）， and Fc receptor like B （FCRLB）； and 6 downregulated genes： STEAP4 metalloreductase （STEAP4）， pleckstrin homology domain containing family F member 2 （PLEKHF2）， CD3d molecule （CD3D）， transgelin 2 （TAGLN2）， tripartite motif containing 22 （TRIM22）， and ribosomal protein L9 （RPL9）. The biological function analysis results indicated that these genes were mainly involved in pathways such as iron ion transport into the cells， oxidoreductase activity， primary immunodeficiency， and Th1 and Th2 cell differentiation. The MR analysis results confirmed the causal relationship between these targets and COPD. The external validation results showed that compared with healthy controls， the expression level of FCRLB in COPD samples was significantly increased （P<0.01）， while the expression levels of CD3D and RPL9 were significantly decreased （P<0.05 or P<0.01）， which was consistent with the MR analysis results， highlighting the reliability of this study. Conclusion DGKG， NEFH， FCRLB， STEAP4， PLEKHF2， CD3D， TAGLN2， TRIM22， and RPL9 may serve as important regulatory factors and clinical diagnostic/therapeutic targets in the pathogenesis of COPD， providing clues for early screening， diagnosis， and targeted treatment of COPD.

Key words: Chronic obstructive pulmonary disease, Mendelian randomization, Gene Ontology functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes signaling pathway enrichment analysis, Biomarker, Bioinformatics