Gene structure and expression

Do people with CFS have differences in the way their genes are built—from inheritance— compared to health controls? Is there a difference in which genes are “turned on” (expressed)? Is there a relationship between these differences and the underlying biology of this illness?

Dr. Komaroff reviewed a selection of genomic and genetic research presentations from the Ottawa conference which exemplify how this science and tools can help to identify patterns unique to CFS.  It is important to note many other fields are using gene expression patterns/results in their studies to evaluate CFS compared to healthy controls or other illnesses.

Gene structure

Gene structure in CFS was assessed by Dr. M.S. Rajeevan, with the CDC, by using community-based samples and comparing these to healthy controls. This study reported polymorphisms in genes that are involved in the immune response—more specifically, complement cascade, chemokine production and toll-like receptor signaling—which were different in CFS patients. Basically, this study demonstrates how changes in gene sequences detected could determine that these genes played a role in innate immune response.

Dr. Lea Steele, at Baylor University, combined an epidemiological study with molecular biology, and identified two polymorphisms that reduced the body’s ability to degrade nerve gases and pesticides, respectively. These polymorphisms were found to correlate strongly with the presence of Gulf War Syndrome in individuals who had been military personnel exposed to those environmental toxins, and not in those unexposed. Steele’s study also showed a dose-response relationship with homozygotes of these polymorphisms had a clearer, more severe form of GWS compared to heterozygotes (per Dr. Komaroff’s IACFS/ME Meeting Highlights PowerPoint slides on Gene Structure). Dr. Komaroff remarked that it remains to be seen whether these results in GWS will have any relevance to CFS/ME or Fibromyalgia.

Gene expression

A mini primer on gene expression, prepared by Dr. Komaroff, was helpful in getting across the basic aspects of this science, in this way:

Genes are only important if they are “expressed”, or “turned on” and are making messenger RNA.  The central process can be stated as follows:

DNA→ makes messenger-RNA (mRNA)→ makes Protein.

DNA not only makes full-length genes but also makes tiny microRNAs, which feed back on specific mRNAS and interfere with protein production. Consequently, they block protein production—the result is they “turn off” the gene.

A method of detecting gene expression is using a tool called microarrays, which allow for extensive analysis of many genes at one time (up to 22,000). This technique makes it possible to take a tissue and be able to tell which genes are turned on and off. Microarray tests are performed on silicone chips, and when a gene sequence finds its complementary match on the chip (when there is a fit), they will light up—the patterns of genes that are “turned on” help to make many inferences about what is going on.

Gene Expression studies

The importance of gene expression can be demonstrated in this preliminary study that had found 6 miRNAs to be substantially down-regulated in both NK-cells and CD8+ cells in CFS patients, compared to healthy controls. These cells play a critical role in antiviral activities and have been shown to function defectively in CFS in previous studies. These miRNAs regulate the expression of genes involved in cell cycle regulation, apoptosis, and toll-like receptor expression (EW Brenu).

An exercise challenge test, conducted at University of Miami, confirmed an enhanced alteration in the expression patterns of a group of genes, as previously found in ME/CFS by Dr. John Kerr from the U.K. (i.e, the Miami study used the Kerr ME/CFS platform to evaluate gene expressions). The genes that were altered are those which play important roles in antiviral defense, mitochondrial function, and immune activation. The same changes were not seen in healthy controls or patients with Gulf War Illness. (L Garcia)

Dr. G. Broderick used data from Dr. Katz’s study of adolescents with infectious mononucleosis and post-mono CFS, and his study could identify biological pathways that are up-regulated or down-regulated. Children with post-mono CFS had 5 signaling pathways with altered activity, most notably, the phenylalanine metabolic pathway which was down-regulated. Patients with greater down-regulation had greater fatigue—a “dose-response” relationship (Broderick, Katz, Taylor).

Dr. Lucinda Bateman presented research done by Dr. Alan Light and Dr. Kathleen Light that looked for changes that exercise would make in gene expressions, in patients with CFS, CFS and Fibromyalgia (FM), FM only, Multiple Sclerosis (MS), and in healthy controls. (CFS and FM patients used in this study were referred by Dr. Bateman, clinical collaborator.)

Dr. Bateman reported that both patient self-rated and physician-rated symptom severity correlated with greater post-exercise increases in these genes. However, a subgroup (about 30%) of patients did not demonstrate such gene expression changes and the clinical clue for difference was the history of orthostatic intolerance in this subgroup. Results seen in CFS patients were not seen in healthy controls, FM only, or MS.