Multi-omics analysis reveals the molecular mechanisms and therapeutic targets in high altitude polycythemia

Polycythemia, characterized by an abnormal increase in red blood cells, can manifest as primary polycythemia (PV) or secondary polycythemia, often due to conditions like obstructive sleep apnea (OSA) and high-altitude polycythemia (HAP). Understanding the molecular mechanisms underlying these conditions is crucial for developing targeted therapies. Transcriptome analysis was performed to identify differentially expressed genes (DEGs), significant modules, and immune cell infiltration. We identified 370 DEGs and four significant gene co-expression modules closely related to HAP. Modules were associated with neutrophil migration, glycoprotein metabolism, UDP-N-acetylglucosamine synthesis, and red pulp cells. These modules showed the same directions of change in OSA but were reversed when treated with continuous positive airway pressure therapy. Comparison with GWAS showed that overlapping genes were related to oxygen transport in the DEGs. PRDM1 and NCOA1, NFE2 were identified as key transcription factors. Noca1 knockout mice showed elevated levels of red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT). Lomustine and hydralazine emerged as potential candidate drugs for treating polycythemia. Abdominal breathing training for three months improved symptoms and reduced RBC, HGB, and HCT in 33 HAP patients. These findings elucidate HAP's molecular mechanisms and suggest new therapeutic directions.