Implications of Genes Involved in Inflammatory Regulation, Cytoskeletal Organization, and Extracellular Matrix Integrity for Susceptibility to High-Altitude Pulmonary Edema: A Pilot Whole-Exome Sequencing Study.

High-altitude pulmonary edema (HAPE) is a potentially fatal form of non-cardiogenic pulmonary edema that develops in susceptible individuals following rapid ascent to high altitude. Although exaggerated hypoxic pulmonary vasoconstriction is central to its pathophysiology, additional physiological mechanisms may also underlie individual susceptibility to HAPE. Whole-exome sequencing (WES) enables the identification of coding variants that may contribute to disease susceptibility. This pilot study evaluated the utility of WES for identifying coding variants associated with HAPE susceptibility. WES was performed in eight Japanese individuals: four HAPE-susceptible (HAPE-s) subjects and four HAPE-resistant (HAPE-r) mountaineers with repeated high-altitude exposure. Initial variant filtering prioritized coding variants present in all HAPE-s subjects but absent in HAPE-r controls. Additional stringent filtering was subsequently applied to identify variants significantly enriched in HAPE-s subjects compared with allele frequencies in the Japanese reference population from the Human Genetic Variation Database. Gene Ontology enrichment analysis was performed to characterize the biological processes associated with the identified genes. Fifteen coding variants were identified significantly in HAPE-s individuals. Gene Ontology enrichment analysis demonstrated enrichment of biological processes associated with inflammatory regulation, cytoskeletal organization, and extracellular matrix (ECM) organization, suggesting that altered inflammatory responses and pulmonary structural properties may contribute to HAPE susceptibility. These findings suggest that genetic variants affecting inflammatory signaling, cytoskeletal organization, and ECM integrity may influence endothelial permeability and alveolar-capillary barrier function, thereby increasing susceptibility to HAPE. These preliminary results support the hypothesis that physiological mechanisms beyond exaggerated hypoxic pulmonary vasoconstriction also contribute to HAPE pathophysiology. Further studies in larger cohorts and functional analyses are warranted to confirm these observations and elucidate the underlying physiological mechanisms.