In multiple sclerosis, the immune system attacks important components of the brain and spinal cord. Over time, nerve conductions are destroyed and sufferers lose the ability to move under their own power. Researchers have now identified a genetic variant that is associated with a particularly rapid progression of the disease. At the same time, the study indicates that the resilience of the attacked nervous system could play an important role. This could help to develop new therapies that slow the progression of multiple sclerosis.
Around 2.8 million people worldwide suffer from multiple sclerosis (MS). In this autoimmune disease, a misguided immune response is directed against the lining of the nerve fibers of the brain and spinal cord. Because this myelin sheath is essential for nerve conduction, this results in sensory disturbances and an increasing loss of mobility in those affected. Previous therapies primarily aim to suppress the harmful immune reaction. Although they can alleviate acute flare-ups of the disease, they do not prevent the disease from progressing. It is also unclear why the disease progresses relatively quickly in some MS patients, while others can live with it for years or even decades without major impairments.
Search for clues in the genome
In order to better understand the basics of multiple sclerosis and thus create a basis for future treatments, a team led by Adil Harroud from the University of California in San Francisco has set out to search for clues in the genome. To do this, the researchers analyzed data from more than 12,000 people with multiple sclerosis in a genome-wide association study. Genetic variants are associated with certain characteristics, in this case with a fast or slow progression of the disease.
Among more than seven million genetic variants, the team discovered one associated with faster disease progression. "If you inherit this genetic variant from both parents, the time until you need a walker speeds up by almost four years," reports Horroud's colleague Sergio Baranzini. In addition, the brains of carriers of the variant showed more abnormalities typical of the disease than people without the variant, although a similar amount of time had passed since the MS diagnosis in both. In people with only one copy of the variant, the disease progressed only slightly faster than in those without the variant.
Brain resilience influences course
The newly identified gene variant lies between two genes that have not previously been associated with multiple sclerosis. One gene, DYSF, is involved in repairing damaged cells, and the other gene, ZNF638, plays a role in controlling viral infections. "These genes are normally active in the brain and spinal cord and not in the immune system," explains Harroud. The scientists conclude from this that the gene variant does not affect the disease-causing immune processes themselves, but rather the reaction of the attacked tissue. "Our results suggest that resilience and repair capacity in the nervous system determine the course of MS progression and that we should focus on these parts of human biology to find better therapies," said Harroud.
The team also identified other factors that influence the course of the disease. Among other things, the analysis confirmed that smoking accelerates the worsening of symptoms. Contrary to previous assumptions, the researchers found no connection to the severity of the disease for the vitamin D level and the body mass index of those affected. On the other hand, it was found that the disease progressed more slowly in people with a higher level of education. "Although it seems obvious that the brain's resilience to damage determines the severity of a disease like MS, this new study has pointed us to the key processes underlying this resilience," says co-author Stephen Sawcer from the University of Cambridge. The team confirmed the results with data from almost 10,000 other MS sufferers.
In future studies, the researchers want to examine in more detail what influence the genetic variant has on the functioning of neighboring genes and on the resilience of the nervous system. "This gives us the opportunity to develop new medicines that could help keep all MS patients healthy," said Harroud.
Source: Adil Harroud (University of California at San Francisco) et al., Nature, doi: 10.1038/s41586-023-06250-x