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(Circulation. 2002;106:826.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Positive Association of the Endothelial Nitric Oxide Synthase Gene Polymorphisms With High-Altitude Pulmonary Edema

Yunden Droma, MD; Masayuki Hanaoka, MD; Masao Ota, PhD; Yoshihiko Katsuyama, PhD; Tomonobu Koizumi, MD; Keisaku Fujimoto, MD; Toshio Kobayashi, MD; Keishi Kubo, MD

From the Departments of Medicine (Y.D., M.H., T. Koizumi, K.F., T. Kobayashi, K.K.), Legal Medicine (M.O.), and Pharmacy (Y.K.), Shinshu University School of Medicine, Matsumoto, Japan.

Correspondence to Masayuki Hanaoka, MD, First Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail masayuki{at}hsp.md.shinshu-u.ac.jp

Background— A defect of nitric oxide (NO) synthesis in the lung of high-altitude pulmonary edema (HAPE) has been suggested to contribute to its exaggerated pulmonary hypertension. Several polymorphisms have been identified in the gene encoding endothelial nitric oxide synthase (eNOS), which is a key enzyme responsible for NO synthesis, some of which were reported to be associated with vascular disorders.

Methods and Results— We studied 41 HAPE-susceptible subjects (HAPE-s) and 51 healthy climbers (control group) in a Japanese population. We examined 2 polymorphisms of the eNOS gene, including the Glu298Asp variant and 27-base pair (bp) variable numbers of tandem repeats using polymerase chain reaction followed by restriction fragment length polymorphism. The Asp allelic frequency of the Glu298Asp variant was 25.6% in the HAPE-s and 9.8% in the controls, which was significantly different between the two groups (P=0.0044). The eNOS4a allelic frequency of 27-bp variable numbers of tandem repeats was 23.2% in the HAPE-s, significantly higher than that of 6.9% in the controls (P=0.0016). In HAPE-s group, 11 of 41 (26.8%) subjects possessed simultaneously both of the two significant alleles, but among the controls, none did, which showed a high statistical difference between the two groups (P=0.000059).

Conclusions— Both polymorphisms of the eNOS gene were significantly associated with HAPE. A genetic background may underlie the impaired NO synthesis in the pulmonary circulation of HAPE-s. These polymorphisms could be genetic markers for predicting the susceptibility to HAPE.

Key Words: hypoxia • hypertension, pulmonary • genes • nitric oxide synthase

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