Background: This study aimed to evaluate the potential of krebs von den lungen-6 (KL-6) as a biomarker for distinguishing emphysematous chronic obstructive pulmonary disease (COPD-E) from non-emphysematous COPD (COPD-NE), and to explore the underlying mechanisms associated with KL-6 expression.

Methods: We enrolled 154 patients with COPD and 170 healthy controls to assess serum KL-6 levels. ROC was used to determine the diagnostic sensitivity and specificity. Univariate and multivariate linear regression analyses were performed to explore the factors influencing KL-6 levels in COPD. Transcriptomic sequencing was performed on PBMCs from COPD patients with varying KL-6 levels to explore underlying biological mechanisms. A Mendelian randomization analysis was employed to ascertain the association between the expression quantitative trait loci of key genes and emphysema risk.

Results: Serum KL-6 levels were significantly elevated in COPD-E patients compared with COPD-NE. Transcriptomic analysis revealed 237 DEGs between patients with high and low levels of KL-6. Gene set enrichment analysis revealed that these DEGs were associated with immune responses. No significant difference in immune cell infiltration was observed between high and low KL-6 groups, but KL-6 showed a negative correlation with T cell gamma delta. By intersecting the DEGs with those from the GSE248493 dataset, we identified seven key genes and further validated their association with the risk of emphysema using Mendelian randomization, with AMDHD2 potentially reducing the risk of the disease.

Conclusions: KL-6 is a promising biomarker for distinguishing COPD-E from COPD-NE and AMDHD2 may be involved in the regulation of increased KL-6 levels in COPD-E.

Qian Zhang received his Ph.D. degree in Pulmonary Medicine from Nanjing Medical University, P.R. China. From 2011 to 2016, he worked as a postdoctor in Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu Province, P.R. China. Currently, he is working as chief physician, professor and director in the department of respiratory medicine at Changzhou No.2 People’s Hospital affiliated to Nanjing Medical University. He is interested in pulmonary medicine, critical care medicine, molecular biology, allergy and immunology.