Xinru Xiao,1,* Wenwen Guo,1,* Na Li,1 Nuo Chen,1 Qian Zhang1,2 

1Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, People’s Republic of China; 2Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Qian Zhang, Email qianzhang@njmu.edu.cn

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. Receiver operating characteristic curve was used to determine the diagnostic sensitivity and specificity. Pearson’s correlation analysis was used to evaluate the correlation. Univariate and multivariate linear regression analyses were performed to explore the factors influencing KL-6 levels in COPD. Transcriptomic sequencing was performed on peripheral blood mononuclear cells 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 patients, particularly in COPD-E. Pearson analyses revealed that the serum KL-6 concentration was positively correlated with eosinophil count. Transcriptomic analysis revealed 237 differentially expressed genes (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 proportions were 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 amidohydrolase domain containing 2 (AMDHD2) potentially reducing the risk of the disease.
Conclusion: 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.

Keywords: chronic obstructive pulmonary disease, emphysema, Krebs von den lungen-6