Researchers from Japan found that two slight variations in a gene that helps maintain lung function can increase the risk of a form of altitude sickness called high-altitude pulmonary edema (HAPE). The condition occurs in persons rapidly going to altitudes higher than 8,175 feet, especially when they are exerting themselves.

The research team compared 41 subjects with a history of HAPE and 51 healthy subjects, checking their blood samples to determine the DNA sequence of a gene known as eNOS, or endothelial nitric oxide synthase. A crucial enzyme involved in the release of nitric oxide in the blood vessels, eNOS regulates the blood vessels' tone by causing them to dilate, thus increasing blood flow.

"It has already been known for a long time that high pulmonary artery pressure plays a central part in the development of HAPE," which is mainly caused by pulmonary constriction, says lead author Dr. Masayuki Hanaoka, a specialist in high-altitude medicine at the Shinshu University School of Medicine in Matsumoto, Japan. Nitric oxide is a strong and effective dilator of blood vessels and has many biological functions in the body, says Hanaoka, whose study appears in today's online issue of Circulation.

Previous research has demonstrated that nitric oxide was defective in the lungs of HAPE victims, and that it was synthesized by the eNOS gene. "So, it is a reason for us to suspect the gene for encoding nitric oxide probably has some mutations," he says.

Their suspicions were correct. They found striking differences between the healthy subjects and those with a history of HAPE. They had two different polymorphisms -- variations -- in the gene, and some had both variations. They found that 25.6 percent of the HAPE group had a variation designated Glu298 Asp, compared with just 9.8 percent of the control group.

They also found that 23 percent of those who suffered from HAPE had the second variation of the gene, called 27-bp VNTR. Only 6.9 percent of the controls had that one. The researchers further found that 26.8 percent of the HAPE subjects had both variations, as opposed to none of the controls.

"The most important finding in our study are the significant positive associations of the two genetic polymorphisms in the eNOS gene with individuals susceptible to HAPE," Hanaoka says. The potential risk, he adds, might be greater in those who have both variations rather than just one.

HAPE, a form of severe altitude sickness, has puzzled physicians and researchers for years, partly because it's so difficult to predict who might get it. Age is not a predictor, nor is fitness.

Symptoms include extreme fatigue, breathlessness, shallow and fast breathing, coughing, chest tightness, and blue or gray lips or fingernails. Immediate descent, along with oxygen and drugs, is necessary, since death occurs in 44 percent of the people who are not treated.

"It's a very good study," says Dr. Charles S. Houston, a retired professor of environmental medicine at the University of Vermont and the author of several books on altitude sickness. "The finding may be significant."

While the report is believed to be the first to associate the eNOS gene variation with HAPE, Houston says researchers have suspected a genetic predisposition to the condition for several years.

Next, the Japanese team hopes to replicate the study with other populations.

Meanwhile, Hanaoka says, tests showing the presence of the gene variation does not mean someone will always contract the disorder when ascending to high altitude, only that the possibility or relative risk is higher than for someone without the faulty gene.

What To Do

For information on HAPE, click on the High Altitude Medicine Guide or the International Society for Mountain Medicine.