Abstract
High-altitude populations exhibit lower cardiovascular disease incidence and mortality with significant differences between indigenous highlanders and migrants. However, related genetic adaptation and population-specific mechanisms remain underexplored. We conducted a comprehensive multi-omics investigation of three cardiovascular disease patient cohorts from distinct altitudes: indigenous high-altitude residents (IHA, n = 31), high-altitude migrants (HAM, n = 18), and low-altitude residents (LAR, n = 50). IHA cardiovascular patients exhibited distinctive genetic signatures with significant enrichment of UGT1A family gene variants. Lipidomic profiling identified 118 differential lipid species between IHA and HAM patients, with significant enrichment in sphingolipid metabolism pathways. Integration of genomic and lipidomic data identified 102 significant gene-metabolite associations in IHA patients, particularly between UGT1A variants and sphingomyelin species. Comparative analysis with LAR patients revealed both shared and population-specific metabolic signatures. Our findings offer unique perspectives on cardiovascular disease in high-altitude environments, revealing complex interactions between genetic adaptation, environmental exposure, and disease pathophysiology.