Single-cell hdWGCNA reveals a novel diagnostic model and signature genes of macrophages associated with chronic obstructive pulmonary disease.

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory system-related mortality worldwide. Although COPD is associated with immune regulation, its underlying mechanisms remain unclear.

Methods: Cells from the single-cell RNA sequencing (scRNA-seq) datasets were subjected to clustering analysis and cell type identification to isolate immune cell subgroups specifically expressed in COPD. High-dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify hub genes related to the immune cell subpopulations. Machine learning algorithms were applied to identify diagnostic genes in the immune cell subpopulations and construct clinical diagnostic models for COPD. In bulk RNA sequencing data, AUC curves were used to assess the stability of the diagnostic models in predicting COPD.

Results: Through 2 rounds of clustering analysis, the macrophage subgroups 1, 2, 7, 11, and 13 which specifically expressed in COPD (COPD_Mφ) were identified. HdWGCNA analysis revealed a hub set of genes closely related to COPD_Mφ from black, blue, yellow, and brown modules. Nonnegative Matrix Factorization (NMF) analysis separated the COPD samples into 2 clusters, with significant increases in the infiltration of Monocytic_lineage, Myeloid_dendritic_cells, and Neutrophils in cluster 1 (P < 0.001). Univariate logistic regression and LASSO regression analyses identified 11 feature genes associated with COPD_Mφ, including CST3, LGALS3, CSTB, S100A10, CYBA, S100A11, ARPC3, FTH1, PFN1, MAN2B1, and RPL39. The RF and convolutional neural network (CNN) models constructed using these feature genes effectively distinguished between normal and COPD patients. Among them, S100A10, RPL39, and FTH1 exhibited differential expression between COPD patients and normal individuals and could serve as potential clinical diagnostic markers for COPD.

Conclusions: The study provides new insights into the immune mechanisms of COPD and lays the theoretical foundation for its future clinical diagnosis and personalized treatment.