Genetic Associations with the Susceptibility to High-Altitude Pulmonary Edema in the Japanese Population

Yunden Droma, Masao Ota, Nobumitsu Kobayashi, Michiko Ito, Toshio Kobayashi, and Masayuki Hanaoka. Genetic associations with the susceptibility to high-altitude Pulmonary Edema in the Japanese population. High Alt Med Biol. 26:215–226, 2025.—High-altitude pulmonary edema (HAPE) is a life-threatening, noncardiogenic pulmonary condition that may occur in individuals rapidly ascending to altitudes higher than 2,500 m above sea level. Exaggerated hypoxia-induced pulmonary hypertension plays a critical role in its pathophysiological mechanism. In addition to environmental factors such as hypoxia and hypobaria at high altitudes, individual genetic predisposition significantly influences HAPE occurrence. Several candidate genes have been proposed based on the pathophysiology of HAPE, particularly involving the hypoxia-induced factor pathway and vasodilators/vasoconstrictors. Over the past two decades, we have investigated the associations between susceptibility to HAPE and these candidate genes, including genes EPAS1 (endothelial Per-ARNT-Sim [PAS] domain protein 1), EGLN1 (egl-9 family hypoxia inducible factor 1), eNOS (endothelial nitric oxide synthase), ACE (angiotensin-converting enzyme), and TIMP3 (tissue inhibitor of metalloproteinase 3) in the Japanese population. This review summarizes the major findings of these studies, shedding light on genetic associations with HAPE in the Japanese population.