From Chronic COVID to MS: Shared Biological Link Found Among Five Disabling Diseases

Scientists analyzing the genome in three dimensions have found that five disabling diseases, despite having different roots, stem from shared biological pathways and networks.

For some people, getting out of bed and doing everyday tasks can be as difficult as digging yourself out of a swamp. Severe and persistent fatigue is one of the main symptoms of chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME); This disease can also be associated with cognitive problems such as "brain fog".

However, chronic and long-term fatigue is a central feature of several other debilitating diseases, including chronic COVID, post-traumatic stress disorder (PTSD), rheumatoid arthritis (RA), and multiple sclerosis (MS).

According to Zomit, chronic covid is caused by a viral infection, although the same possibility has also been suggested for CFS/ME. PTSD stems from traumatic experiences and is linked to chronic inflammation, while RA and MS are known to be autoimmune disorders in which the body mistakenly destroys its own tissues.

Now researchers from the University of East Anglia and Oxford Biodynamics, a biotech company that designs commercial molecular diagnostic tests, say they have uncovered common underlying mechanisms among the five diseases, ScienceAlert reports. Despite the wide pathological differences, the overlap in the symptoms reported by the patients formed the main focus of the research.

Patients with five different diseases often report very similar symptoms

"What links all these diseases together is that patients often report very similar symptoms; Exhausting fatigue, brain fog, decreased concentration, sleep disorder, dysfunction of the autonomic nervous system and a significant decrease in the ability to perform daily activities. We wanted to know why this is happening."

To find the answer, the researchers pooled data from existing genome-wide association studies (GWAS). These studies, which have examined the association between different genetic variants and diseases at the population level, include data from thousands of cases of each of the five diseases.

Then the researchers went to the Episwitch platform; A set of machine learning algorithms previously used to develop a CFS/ME blood test prototype. This platform allowed researchers to look beyond the linear DNA sequence and consider the 3D architecture of the genome; That is, how genes located on different parts of DNA interact with each other in the three-dimensional space of the cell. The shape of chromosomes and epigenetic changes are among the factors that can affect this structure.

"What we discovered looks like a biological, unified theory of fatigue," says Pszetsky.

Although there was very little direct overlap between the genes associated with each disease, all five diseases appeared to be related to each other at a deeper level. Genes associated with any disease, like several streams pouring their sediments into a river, eventually end up in common biological networks.

By analyzing the networks, the researchers identified some very effective "gene hubs"; Genes that are located in the most crowded parts of the networks. More laboratory and clinical validation is still needed to confirm the connection of genes with each of the diseases, but these genes and related pathways are involved in important processes such as immune and inflammatory reactions, hormonal signaling under the control of the brain, and energy production in mitochondria. These processes were previously associated with ME/CFS and chronic covid.

Importantly, many hub genes were not identified as significant variants in the genome-wide association data. "It's not something that can be proven just by reading the genetic sequence," Pszetsky says. For this reason, the diseases may have been considered unrelated for a long time.

The study also highlighted "immune cell exhaustion" as a potential mechanism for the link between the five diseases. "The findings suggest a state of chronic activation of the immune system followed by functional exhaustion that may contribute to the persistence of symptoms," the researchers wrote in the paper.

If the results are confirmed in further studies, the researchers hope to use the findings to develop laboratory-based diagnostic tests for CFS/ME and chronic Covid, rather than relying solely on patient-reported symptoms.

Exhaustion of immune cells was proposed as a potential mechanism for the connection between the five diseases

However, the research faces some limitations. The genetic associations identified in the study were extracted from genome-wide association data; Information that is limited to only certain population groups and covers a very small part of the functional genome. In addition, many regulatory elements are located in the "dark" and non-coding regions of DNA.

The EpiSwitch platform evaluates epigenetic changes by analyzing the 3D structure of the genome; Processes that are able to change the way DNA is packaged and thus the expression of genes. The changes seem to be a reflection of exposure to environmental factors, such as stress and infections, and although they are not permanent, they leave long-term consequences.

Pszetsky hopes the study will pave the way for the development of accurate blood tests that measure underlying biomarkers instead of relying on individual patient reports. In addition, such research may in the future help to invent new therapeutic methods to inhibit hyperactive immune cells or strengthen the ability of mitochondria to produce energy.

The research was published in the Journal of Translational Medicine.