Faulty Gene May Explain Why Some Fall Ill At High Altitudes

The findings may also help researchers find causes of other lung disorders. These include chronic mountain sickness, primary pulmonary hypertension, emphysema and chronic bronchitis.

High-altitude pulmonary edema (HAPE) occurs in seemingly healthy people after rapid exposure to altitudes higher than 2,500 meters (8,175 feet), particularly when the people exert themselves.

HAPE causes fluid in the lungs, difficulty breathing, severe weakness and dangerously rapid heartbeats. Death occurs in 44 percent of people who are not treated with oxygen or drugs, or moved to a lower altitude. About 1 percent of the Japanese population is susceptible to the condition.

Researchers first recognized HAPE as a specific disorder in 1960. Before that, people who experienced its symptoms were diagnosed as having pneumonia or heart failure. "It is a hazard to mountaineers, trekkers, skiers and people moving to high altitudes," says study co-author Masayuki Hanaoka, M.D., Ph.D., a specialist in high-altitude medicine at Shinshu University School of Medicine in Matsumoto, Japan.

Japanese researchers found that two variations, or polymorphisms, in the endothelial nitric oxide synthase (eNOS) gene occurred significantly more often in people who suffered HAPE than in a group of mountain climbers who had never experienced the condition. eNOS is a key enzyme involved in the release of nitric oxide in the blood vessels. Nitric oxide regulates the tone of blood vessels by causing them to relax, or dilate, to increase blood flow. Drugs called vasodilators that elicit this response in blood vessels can prevent HAPE as well as treat it.

"This is the first report of a positive genetic association of the eNOS gene with HAPE," Hanaoka says. "The eNOS polymorphisms identified may help predict susceptibility to HAPE."

Although the exact mechanism by which HAPE develops is unclear, "We postulate that the production of nitric oxide in the blood vessels of the lungs may be impaired in HAPE as a result of the polymorphisms in the eNOS gene. Further studies are necessary to clarify this proposition," Hanaoka says.

Confirming the genetic link could also lead to new treatments and perhaps prevention, Hanaoka says.

"It is not a dream to think about transferring the healthy eNOS gene to the human lung to compensate for the insufficient production of nitric oxide," he says.

Abnormal constriction of vessels in the lungs appears to contribute to HAPE, and studies have shown that HAPE patients have reduced nitric oxide in their lungs.

"We did this study to try to decipher the genetic cause of the nitric oxide deficit in patients with HAPE," Hanaoka says.

Researchers drew blood from 41 healthy climbers with a history of HAPE and a control group of 51 healthy climbers from the Mountaineering Association of Nagano and the Alpine Club of Shinshu University who had no history of HAPE. The HAPE group was healthy and athletic at low altitudes but suffered HAPE that required hospitalization at least once while mountain climbing. The control group, on average, had made more than 100 climbs at elevations exceeding 2,800 meters (9,186 feet) above sea level without experiencing HAPE.

All participants were Japanese, unrelated to one another, and were born and lived at elevations of less than 610 meters (2001 feet).

Using the blood samples, researchers determined the DNA sequence of the eNOS gene in each participant. They found significant differences between the HAPE patients and the control group in two variations – designated Glu298Asp and 27-bp VNTR – that occur in the gene.

Only 9.8 percent of the control group carried the Glu298Asp variation compared to 25.6 percent of the HAPE patients. Variations at the 27-bp VNTR site on the gene occurred in 6.9 percent of the control group and in 23.2 percent of the HAPE patients.

The researchers then investigated how many of the 92 participants had both variations. They found that 26.8 percent of the HAPE group, but none of the control group, carried the two polymorphisms.

Co-authors are Yunden Droma, M.D.; Masao Ota, Ph.D.; Yoshihiko Katsuyama, Ph.D.; Tomonobu Koizumi, M.D.; Keisaku Fujimoto, M.D.; Toshio Kobayashi, M.D.; and Keishi Kubo, M.D.