Chronic Fatigue's Genetic Component
Friday, April 21, 2006
An intense battery of medical and psychological tests of people with chronic fatigue syndrome has strengthened the idea that the mysterious ailment is actually a collection of five or more conditions with varying genetic and environmental causes, scientists reported yesterday.
But though the syndrome comes in many flavors, these experts said, the new work also points to an important common feature: The brains and immune systems of affected people do not respond normally to physical and psychological stresses.
The researchers predicted that continued clarification of the precise genes and hormones involved will lead to better diagnostic tests and therapies for the ailment, which may affect close to 1 million Americans.
"This is a very important step forward in the field of chronic fatigue syndrome research," said Julie L. Gerberding, director of the federal Centers for Disease Control and Prevention in Atlanta, which sponsored the project.
The new findings come from the largest clinical trial ever to focus on people with the syndrome, a debilitating condition accompanied by unexplained extreme fatigue, memory and concentration problems, sleep disorders and chronic pain.
Taking a multidisciplinary approach that agency officials said represents the future of public health, the CDC recruited 20 physicians, molecular biologists, epidemiologists, computational biologists -- even physicists and mathematicians -- to collaborate in an effort to tease apart the syndrome.
The results, published in more than a dozen reports and commentaries in the April issue of the journal Pharmacogenomics, released yesterday, suggest that many cases of chronic fatigue have links to a handful of brain- and immune system-related genes that either harbor small mutations or are working abnormally for other reasons.
That finding strengthens the case that some people are born with a predisposition to the condition. But those genetic links remain weak and incomplete, researchers conceded, leaving most of the syndrome's roots hidden in a fog of poorly understood physiological, neurological, psychological and behavioral factors.
"Chronic fatigue syndrome is very heterogeneous. It's not just one thing," said William C. Reeves, who oversaw the project with CDC co-worker Suzanne D. Vernon. It will take time to identify all the biological pathways involved, Reeves said, but the growing evidence of genetic links should put to rest the idea that the syndrome is a made-up diagnosis for "a bunch of hysterical, upper-class white women."
The new study involved 227 residents of Wichita, Kan., who spent two full days in a hospital undergoing a series of blood tests, hormone studies, psychological exams and sleep studies.
About one-quarter of them met the formal definition of chronic fatigue syndrome. A similar number proportion had chronic fatigue but did not rank as having the full-blown syndrome -- in many cases because their fatigue was not severe enough. A third group met all of the requirements of the syndrome but also had melancholic depression, which does not fit the current diagnostic guidelines for chronic fatigue syndrome. And a fourth group, for comparison purposes, was healthy.
The CDC, which invested about $2 million in the testing, then made blood-test results and other data available to researchers, who performed a wide variety of analyses.
In one set of studies, scientists looked at the activity levels of 20,000 genes known to be involved in the body's response to such stresses as infections, injuries or emotional trauma. Several hundred were found to be over- or under-active in various subgroups of fatigued patients.
Most of those correlations were weak -- that is, the gene expression patterns alone could not accurately distinguish those whose symptoms had been diagnosed as the syndrome from those whose symptoms had not. But in one analysis, the activity of just 26 genes did accurately predict which of six categories of chronic fatigue a patient had on the basis of symptoms and other clinical tests. That is a powerful hint that those genes -- many of them involved in immune system regulation, the adrenal gland and the brain's hypothalamus and pituitary gland, which are involved in the body's response to stress -- may hold clues to the disease variants.
In other analyses, involving 50 genes that some people inherit with seemingly minor "misspellings," five of the 500 genetic glitches that were tracked repeatedly correlated with an apparent susceptibility to chronic fatigue. Those five include genes that affect levels of serotonin -- the neurotransmitter whose levels are tweaked by many antidepressant drugs -- and glutamate, a chemical that excites certain brain pathways in response to stress.
The specific implications remain uncertain for now, said Vernon, a CDC molecular biologist. "But everybody's finding the same five genes to be involved, which is pretty cool."
Several other studies on the Wichita samples found abnormal levels of various hormones relating to stress and mood -- additional evidence that chronic fatigue syndrome patients are genetically and neurologically "wired" to respond to stress abnormally.
It is already known, Vernon said, that the brain can literally rewire itself -- breaking old connections between neurons while building new ones -- in response to various physical or emotional events. Chronic fatigue syndrome may be the result of a bad rewiring job, she said, in people genetically predisposed to handle stress poorly.