Stanford Report Online

Stanford Report, June 13, 2001
Stanford researchers identify gene associated with sleep apnea


Individuals with a particular genetic marker are twice as likely to suffer from sleep apnea -- a dangerous nighttime breathing disorder -- as people without the gene, say Stanford Medical Center researchers. The gene also predisposes carriers to the development of Alzheimer's and cardiovascular diseases.

The finding marks the first time that a specific gene has been linked to sleep disordered breathing, which may affect up to 10 percent of the population. The researchers say it also suggests that complex interactions exist between breathing patterns during sleep, cholesterol metabolism and mental status.

"What's interesting is that this gene is a marker for dementia and cardiovascular risk," said Emmanuel Mignot, MD, PhD, director of the Center for Narcolepsy at Stanford's Center for Human Sleep Research. "On top of that it also predisposes a carrier to the development of sleep apnea. Since sleep apnea is also linked to cardiovascular disease, there is a snowball effect. This is a marker you really don't want to have."

Mignot, associate professor of psychiatry and behavioral sciences, is the senior author of the research, which is published in today's issue of the Journal of the American Medical Association.

Individuals with sleep apnea repeatedly stop breathing during sleep and must partially wake each time to gasp or snort for air. This sleep/wake cycle can be repeated hundreds of times each night, leading to severe sleep deprivation and daytime drowsiness. Sleep apnea sufferers frequently develop high blood pressure and cardiovascular disease, and they are more likely to die from heart attacks than people without apnea. The disease can cluster in families and studies have shown that Alzheimer's patients are more likely to suffer from sleep apnea than members of the general population.

The Stanford researchers studied a gene called apolipoprotein E, or ApoE, which plays an important role in cholesterol metabolism. Like many genes, its DNA sequence can vary slightly between individuals. ApoE exists in three major varieties: E2, E3 and E4. Previous studies have shown that ApoE4 predisposes carriers to cardiovascular disease and Alzheimer's disease, while ApoE2 seems to offer some protection against developing Alzheimer's. Each person carries two copies of the gene, one inherited from each parent.

Mignot's team analyzed blood samples to determine the prevalence of each version of ApoE in a random pool of 791 middle-aged adults who were part of an ongoing study of sleep disorders. Each of the subjects participated in at least one overnight sleep study to allow researchers to chart the length and frequency of each sleep stage. Researchers also monitored the subjects for signs of sleep apnea, and ranked sleep apnea sufferers based on the severity of their symptoms.

The scientists found that 28 percent of the study subjects carried at least one copy of ApoE4. They also discovered that nearly 12 percent of these ApoE4 carriers also suffered from moderate to severe sleep apnea, compared to only about 7 percent of the non-E4 carriers -- a statistically significant difference. Individuals with two copies of E4 suffered from more severe sleep apnea than did people with only one copy of E4. The association between the presence of ApoE4 and sleep apnea held true even when researchers corrected for other apnea risk factors, including age, gender, body mass and ethnic heritage.

"ApoE4 could account for a significant portion of sleep apnea," said Mignot. He estimates that 50 percent of sleep apnea could be due to genetic factors, and 8 percent may be directly related to the inheritance of at least one copy of ApoE4.

Mignot and the other Stanford researchers believe the association between ApoE4, sleep apnea, cardiovascular disease and Alzheimer's disease is probably not coincidental. Many Alzheimer's patients also experience severe sleep problems, and sleep apnea can be induced by brain injury such as head trauma.

"Sleep apnea may actually be the symptom of a very early form of brain injury," Mignot said. "The plaques in the brain associated with Alzheimer's disease may affect how a person breathes during sleep."

He emphasized, however, that such conclusions are still speculative and need further investigation.

In addition to Mignot, Stanford authors of the paper include Hiroshi Kadotani, MD, PhD; Tomiko Kadotani, MD; Ian Colrain, PhD; and Greer Murphy, Jr., MD, PhD.

Kadotani presented the research last week in Chicago at the annual meeting of the Association of Professional Sleep Societies.