Proteomic study of high-altitude pulmonary hypertension in the Xinjiang Pamir highlanders

BACKGROUND: High-altitude pulmonary hypertension (HAPH), classified as Group 3 pulmonary hypertension, is a significant threat to the health of high-altitude populations. The scarcity of studies in diverse populations has become a research bottleneck, limiting diagnostic and therapeutic advances. METHODS: In this first proteomic study focusing on the eastern Pamir Plateau (Kizilsu Kyrgyz Autonomous Prefecture, Xinjiang), plasma samples were analyzed using data-independent acquisition (DIA) mass spectrometry. Differential expression analysis in parallel with weighted gene co-expression network analysis was performed to identify core pathways and hub proteins, and gene set enrichment analysis was used for quality assessment. Integrative analysis of the two methods was used to select candidates for validation by enzyme-linked immunosorbent assay (ELISA) in an independent cohort. RESULTS: Among > 1400 detected proteins, 123 were differentially expressed and 45 were identified as hub proteins significantly associated with HAPH. Extracellular matrix (ECM) remodeling- and angiogenesis-related proteins were upregulated, whereas proteins related to enzyme activity, iron metabolism, and inflammatory responses were downregulated. Integrative analysis identified 23 core proteins, with ECM-receptor interaction and TGF-β/Smad signaling identified as key pathways. ELISA confirmed that plasma levels of THBS2, LOXL1, and POSTN were significantly elevated in patients with HAPH (P < 0.05). Among these, THBS2 and LOXL1 levels were positively correlated with mPAP (THBS2: r = 0.389, 95% CI: 0.034-0.657, P = 0.033; LOXL1: r = 0.457, 95% CI: 0.115-0.701, P = 0.011). CONCLUSIONS: ECM remodeling is closely associated with HAPH in this indigenous high-altitude population. THBS2, LOXL1, and POSTN show potential as biomarkers and therapeutic targets.