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February 26, 2026Scientific Reports0 citationsOpen Access

Unveiling key pathways and potential biomarkers for high-altitude hypertension: a pilot multi-omics study

JHJu HuangZDZhuoga DanzengLGLuobu Gesang

Key Result

The combination of seven biomarkers (CKB, YWHAZ, PI(16:0/16:0), caffeine, plastoquinone 3, 2'-O-methylcajanone, and pseudopelletierine) achieved an AUC of 0.982 for predicting hypertension in Tibetan high-altitude residents.

Key Points

  • This research aims to identify key pathways and potential biomarkers associated with hypertension at high altitudes using metabolomics and proteomics.
  • Included 30 Tibetan hypertension patients and 30 healthy individuals at high altitude (>4500 m).
  • Conducted metabolomic analysis using ultra-high performance liquid chromatography.
  • Performed proteomic analysis using timsTOF Pro2 mass spectrometer.
  • Executed correlation analysis to identify key pathways and biomarkers.
  • Utilized area under the curve (AUC) analysis for hypertension prediction.
  • Identified 87 differentially expressed metabolites and 61 differentially expressed proteins in hypertensive individuals.
  • Caffeine metabolism was significantly impacted, with specific metabolites like Caffeine and Plastoquinone 3 found up-regulated.
  • AUC of 0.871 achieved with a combination of five metabolites for hypertension prediction.
  • Found CKB and YWHAZ as potential protein biomarkers, yielding an AUC of 0.764.
  • Combined metabolomic and proteomic analysis improved AUC to 0.982.

Study Design

Type

Observational (n=60)

Multicenter

Yes

Structured PICO

P
Population
60 Tibetan individuals residing on the Tibetan Plateau at a very high altitude (> 4500 m) in the Nagqu region, including 30 patients with hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg) and 30 healthy controls. Mean age 44.7 years in the hypertension group and 42.7 years in the control group, 70% female. Exclusion criteria: coronary atherosclerotic heart disease, diabetes, chronic obstructive pulmonary disease, heart failure, significant liver and kidney abnormalities, and a smoking history.
C
Comparator
30 healthy Tibetan individuals residing at the same altitude (> 4500 m) as healthy controls
O
Outcome
Identification of key signaling pathways and biomarkers associated with hypertension at high altitude using metabolomic and proteomic analysissurrogate

A multi-omics approach identified a combination of seven metabolite and protein biomarkers that can accurately predict high-altitude hypertension, highlighting the role of lipid metabolism and signal transduction pathways.

Main Result

Effect estimate: AUC 0.982 (95% CI 0.949–1.000)

Limitations

  • Small sample size (N=60) limits statistical power.
  • Only internal validation via PRM technology was performed, external validation is needed.
  • Potential biological variability due to individual genetic backgrounds.
  • Lack of detailed records for timing of initial hypertension diagnosis may introduce heterogeneity.
  • Biological variability arising from individual genetic backgrounds and specificities
  • Small sample size, which constrained the statistical power of tests
  • Lack of detailed records regarding the timing of initial hypertension diagnoses may introduce heterogeneity in disease progression

Abstract

High altitude has a considerable impact on the pathophysiology of the human cardiovascular system and disease occurrence. We aim to use an integrated approach of metabolomics and proteomics to reveal key pathways and biomarkers of hypertension at high altitude. Thirty Tibetan patients with hypertension and 30 healthy individuals residing on the Tibetan Plateau at a very high altitude (> 4500 m) were included in the study. Metabolomic analysis was conducted using Vanquish ultra-high performance liquid chromatography, while proteomic analysis utilized the timsTOF Pro2 mass spectrometer. Correlation analysis revealed key signaling pathways and biomarkers associated with hypertension in Tibetan patients. The results showed 87 differentially expressed metabolites and 61 differentially expressed proteins in individuals with hypertension at high altitude. The results of metabolomic differential metabolite pathway analysis indicated that Caffeine metabolism had the most significant impact. Specific metabolites like PI(16:0/16:0), Caffeine, and Plastoquinone 3 were found to be significantly up-regulated in hypertensive patients. The combination of five metabolites achieved an area under the curve (AUC) of 0.871 for hypertension prediction. Proteomic analysis revealed that the identified differential proteins primarily functioned in signaling receptor binding. It was confirmed that Creatine kinase B (CKB) and Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) could serve as a protein biomarker combination for hypertension in plateau regions, showing an AUC of 0.764 (0.585-0.944). Upon conducting an integrated analysis of metabolomics and proteomics, the combined AUC improved to 0.982 (0.949-1.000). A comprehensive analysis utilizing metabolomics and proteomics revealed that alterations in signal transduction-related pathways and lipid metabolism pathways were implicated in hypertension among plateau populations. Additionally, YWHAZ was observed as a potential biomarker for this condition.

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Cite This Study

Huang et al. (2026) conducted an observational in hypertension at high altitude (n=60). The combination of seven biomarkers (CKB, YWHAZ, PI(16:0/16:0), caffeine, plastoquinone 3, 2'-O-methylcajanone, and pseudopelletierine) achieved an AUC of 0.982 for predicting hypertension in Tibetan high-altitude residents.

synapsesocial.com/papers/699fe24b95ddcd3a253e6287https://doi.org/10.1038/s41598-026-38806-y
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