article: chronic fatigue's genetic component

[Guest guest]

Chronic Fatigue's Genetic Component

Study Clarifies Predisposition to Syndrome

By Rick Weiss

Washington Post Staff Writer

Friday, April 21, 2006; A08

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 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 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.