Altitude-associated circulating biomarker profiles in native Tibetans with and without chronic mountain sickness

Abstract

Aim

Native Tibetans have adapted to chronic hypoxia, yet remain susceptible to Chronic Mountain Sickness (CMS), including high-altitude polycythemia (HAPC) and high-altitude pulmonary hypertension (HAPH). CMS prevalence rises with altitude, but mechanisms remain unclear. We aim to investigate biomarker profiles in native Tibetans with and without CMS across altitudes, including extreme altitude >5,000m.

Methods

We enrolled 91 native Tibetans across 4 altitudes (500 m/3,680 m/4,750 m/5,373 m), categorized into healthy, HAPC and HAPH groups. Seventeen biomarkers were quantified via Luminex. Biomarker associations with altitude and disease were analyzed using linear regression with Type-III-F-tests, followed by post-hoc comparison and effect-size analysis.

Results

Among healthy Tibetans, multiple biomarkers exhibited non-linear altitude-dependent changes. C-X-C motif chemokine ligand 8 (CXCL8), interferon-γ (IFN-γ), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), C-X-C motif chemokine ligand 4 (CXCL4) and thrombopoietin (TPO) peaked at 4,750 m and declined at 5,373 m, whereas matrix metalloproteinase-3 (MMP-3) increased at 5,373 m. Among plateau-dwelling Tibetans (including HAPC and HAPH), no independent main disease-status effects were detected across biomarkers. However, an altitude-disease interaction was observed for angiogenin, with reduction at 5,373 m in HAPH, but not in HAPC.

Conclusion

Rising altitude drives distinct biomarker profiles in healthy Tibetans, with CXCL8/IFN-γ/FGF/VEGF/CXCL4/TPO exhibiting an inverted U-shaped response peaking at 4,750 m, and isolated MMP-3 elevation at 5,373 m, indicating a transition from adaptive angiogenesis to pathological tissue remodeling at extreme-high altitude. The altitude-dependent angiogenin reduction observed exclusively in HAPH at extreme altitude, indicating a dysregulated vascular reparative signaling in Tibetans with HAPH. These findings provide new insights into CMS pathogenesis across hypoxic gradient.