BACKGROUND

Chronic Obstructive Pulmonary Disease (COPD), a complex respiratory disorder, results from genetic and environmental factors. Uncovering its genetic basis is vital for diagnostics and treatment. Robust genetic analysis is essential to establish a causal link.

METHODS

Genome-wide DNA methylation analysis was performed using the Illumina Infinium HumanMethylation850 BeadChip in peripheral blood from 8 COPD patients and 8 healthy smoking controls. Differentially methylated genes (DMGs) were cross-analyzed with differentially expressed genes (DEGs) identified from the Gene Expression Omnibus (GEO) dataset GSE38974 (23 COPD, 9 controls). Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) networks were utilized to identify COPD-associated hub genes. Mendelian randomization (MR) analysis examined the causal relationship between hub genes and COPD. The expression of selected hub genes was validated through RT-qPCR (80 COPD, 62 controls), immunohistochemistry, and Western blot analyses (10 COPD and 10 controls).

RESULTS

We found 10,593 DMGs and 646 DEGs associated with COPD. These genes were compared with WGCNA module genes, and the Protein-Protein Interaction (PPI) network interaction diagram was drawn, thereby identifying five Hub genes: PPIB, HSPA2, PRPF19, FKBP10 and DOHH. The expression levels of DOHH, FKBP10, PPIB and PRPF19 are higher in COPD, while the expression level of HSPA2 is lower. MR results indicate a potential causal relationship between PRPF19, PPIB and COPD. RT-qPCR, immunohistochemistry and Western blot experiments verified that the expression of PRPF-19 and PPIB was up-regulated in peripheral blood and lung tissue, which was consistent with the results of bioinformatics analysis.

CONCLUSION

Our findings suggest that PRPF19 and PPIB may serve as promising diagnostic biomarkers in COPD. Further studies are required to fully elucidate their roles in COPD pathogenesis.