MedPage Today Action Points Explain to interested patients that this research effort has begun to clarify the biological basis of chromic fatigue syndrome. Note that the studies link the syndrome with variations in genes that code for parts of the body's stress response mechanism. Caution that the studies are still preliminary and will need to be replicated. Review ATLANTA, April 20 - Chronic fatigue syndrome (CFS) has been linked to five mutations in three genes that are related to the body's ability to handle stress. "For the first time ever, we have documented that people with CFS have (variations in) certain genes that are related to those parts of brain activity that mediate the stress response," said William Reeves, M.D., director of CFS research at the CDC here. Also, people with the syndrome have differences in genetic activity levels that affect the way they respond to stress accumulated over a lifetime, Dr. Reeves said in a media telebriefing to announce 14 research papers arising from a CDC study in Wichita, Kan. The findings could lead to better diagnostic tools for the syndrome, which is often regarded as ill-defined, and to better treatments, including both cognitive and behavioral therapies and new drugs, Dr. Reeves said. The papers, published in the April issue of the journal Pharmacgenomics, were described as "groundbreaking" by Dr. Reeves, but were not made available to reporters by the CDC. The research "is really the first credible evidence of the biological basis for chronic fatigue syndrome," said CDC director Julie Gerberding. "It reflects a remarkable confluence of a number of scientific advances," she added. The flurry of research papers arose from a longitudinal population-based study in Wichita, from 1997 to 2000. That study found 70 people classified as having CFS, and in 2002 and 2003, they were invited to take part in exhaustive two-day clinical and genetic evaluations. The researchers also included 55 matched controls for the 58 CFS patients who agreed to take part, as well as 59 people with fatigue symptoms who did not meet the full CFS criteria (dubbed ISF). Also, they included 55 people with either ISF or CFS and concurrent melancholic depression. The data gathered from the 227 participants, at a cost of about $2 million, included a full clinical evaluation, electrophysiologic measurements of sleep physiology, cognitive function, autonomic nervous system function, and detailed blood work that included DNA and gene activity analysis, Dr. Reeves said. The next step was to share the data with four teams of researchers, which each took a different approach to the analysis, said molecular epidemiologist Suzanne Vernon, Ph.D., of the CDC's CFS Research Laboratory. For the genetic analysis, she said, "we took a pathway-specific approach. We targeted about 50 genes and 500 polymorphisms in genes that are active in the hypothalamus-pituitary-adrenal (HPA) axis." It turned out that all four groups zeroed in on five single nucleotide polymorphisms (SNPs) in three genes - those coding for the glucocorticoid receptor, for serotonin, and for tryptophan hydroxylase - which, she said, "are very important in the function of the HPA, which is the body's stress response system." The effect of the variations, Dr. Reeves said, appears to be that people with them are less able to cope with stress. One of the research groups, he said, identified three distinct fatigued groups - those with extreme fatigue, those with symptoms such as heart-rate variability and cortisol disturbances, and a group that was primarily menopausal women. "The genes that Dr. Vernon mentioned distinguished the three fatigue groups from those that were not fatigued and two of those genes distinguished between the fatigue groups," Dr. Reeves said. A study such as the one in Wichita produces enormous amounts of data, which must be reconciled if useful conclusions are to be drawn, said Jan Witkowski, Ph.D., director of the Banbury Center at the Cold Spring Harbor (N.Y.) Laboratory. The 14 research papers "are a heroic attempt to do so," he said in an accompanying editorial. But while the amounts of data are large, Dr. Witkowski added, other disciplines have overcome greater challenges and "there is every reason to believe that continuing technical and intellectual advances" will help clarify the basis of diseases such as CFS. Dr. Reeves said the Wichita effort is being followed by a larger study in Georgia, which will attempt to replicate and expand on the results. Primary source: Pharmacogenomics Source reference: Suzanne D. Vernon and William C. Reeves. "The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome." Pharmacogenomics 2006;7:354-354. Additional source: Pharmacogenomics Source reference: J.A. Witkowski. "The post-genomic era and complex disease." Pharmacogenomics 2006;7:341-343.