Deep multi-omics profiling reveals three molecular subtypes of chronic obstructive pulmonary disease in a unique biomass-exposed Chinese population

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. COPD is characterized by progressive airflow restriction and wide-spectrum heterogeneity across clinical manifestations, treatment responses, and underlying mechanisms. While recent omics approaches have advanced our understanding of COPD, in-depth multi-omics characterization remains scarce, leaving a critical gap in knowledge for the understudied population. METHODS: We conducted deep multi-omics profiling on a unique Chinese population from a region with high COPD prevalence, high-altitude residence, and widespread exposure to biomass fuels (74.8%). We recruited 159 COPD patients from 5 medical centers and integrated their radiomics, metabolomics, microbiomics, and genomics data, identifying three distinct molecular subtypes: "stable state" (SS), "restrained state" (RS), and "crumbly state" (CS). FINDINGS: The SS subtype is marked by the least acute exacerbation and mildest airflow limitation with potential eosinophilic inflammation. The RS subtype is characterized by extensive pulmonary structural damage, greatest airflow limitation, but mild clinical symptoms. The CS subtype is typified by disturbed microbial interaction, high triethanolamine, coal dust exposure, and nicotine dependence. CONCLUSIONS: This study provides a comprehensive multi-omics profile of COPD in a previously understudied population and reveals three molecular subtypes that enhance the understanding of COPD heterogeneity.