Multi-omics Identification of Biomarkers for High- altitude Pulmonary Arterial Hypertension

1.1 Background The incidence of High-altitude pulmonary arterial hypertension (HAPAH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed Proteomic and Metabolomic to identify the proteins and metabolic biomarkers that contribute to the development of HAPAH. 1.2 Methods In this study, we conducted an integrated analysis of metabolomics and proteomics using blood samples from patients with HAPAH in the high-altitude regions of Yunnan, China. The findings from the multi-omics data were further validated through animal models. Additionally, we utilized the UK Biobank database to provide further insights and support for the results. 1.3 Results The proteomics sequencing results identified four common differential proteins between paired cohort with HAPAH patients and health control in two high-altitude area (Diqing and Lijiang regions): A2IPH7, K1C14, PSME2, and SERPINE2. Notably, SERPINE2 was significantly downregulated in the HAPAH samples, and its expression exhibited a negative correlation with the clinical indicators of HAPAH. This finding was further validated in Lung histology sections of HAPAH rats. UK Biobank data further confirmed a significant negative correlation between plasma SERPINE2 levels and the occurrence of idiopathicPAH. Metabolomic sequencing identified 11 shared metabolites between the two high-altitude regions, which are primarily categorized into three major types, including acyl fatty acids. These metabolites collectively mediate pathways such as unsaturated fatty acid synthesis. Based on the results from proteomics and metabolomics sequencing, we developed a robust predictive model. 1.4 Conclusion Our study identifies the proteins and metabolic biomarkers that play a crucial role in the development of HAPAH, with validation in animal models. Based on the sequencing results, we also established a predictive model, offering new insights into the prevention of HAPAH. These findings highlight the potential of SERPINE2 and 11 metabolites as promising predictive and therapeutic targets for preventing the onset of HAPAH.