In recent years, there have been many advances in the understanding of the causes of multiple sclerosis: from the description of more than 200 genetic variants associated with the risk of suffering from the disease to the identification of the relationship with Epstein Barr virus infection. Even so, the reasons why some patients progress much more rapidly and severely than others remain unknown. In this regard, a study published in Nature this week presents the first genetic variant linked to a more rapid progression of multiple sclerosis. The work, led by the University of California - San Francisco and the University of Cambridge, has involved Dr. Xavier Montalban, Dr. Manuel Comabella, Dr. Luciana Midaglia and Dr. Sunny Malhotra, researchers from the Clinical Neuroimmunology research group at the Vall d'Hebron Research Institute (VHIR) and the Multiple Sclerosis Center of Catalonia (Cemcat).

Multiple sclerosis is a disease in which the immune system attacks the brain and spinal cord, which is manifested by episodes or outbreaks with a time-limited increase in symptoms, and which also leads to a long-term degeneration of neurons.

In this international study, focused on the study of the progression of multiple sclerosis disability, certain variants in the genome were compared with the evolution of 22,000 patients. In this way, the first genetic variant associated with the severity of the disease was identified: a region located between the DYSF and ZNF638 genes. It was observed that people with two copies of this variant progressed more rapidly with the disease and needed help to walk about four years earlier than people who did not have it.

In relation to the role of these genes, it is known that DYSF is related to the repair of damaged cells in muscles, and that it could play a role in the survival of neurons. ZNF638, on the other hand, is involved in the control of viral infections, with a prominent role in the brain. "These genes are very active in the central nervous system and not so much in the immune system, which tells us that the processes related to the repair and resilience capacity of the nervous system would determine the severity of multiple sclerosis", explains Dr. Manuel Comabella, from the Clinical Neuroimmunology Service at Vall d'Hebron University Hospital, principal investigator of the Clinical Neuroimmunology group at VHIR and head of the laboratory at Cemcat.

The finding presented now offers the opportunity to develop new therapeutic options for patients with multiple sclerosis. "Knowing the mechanisms related to the evolution of the disease will help us to investigate new drugs that block neurodegeneration, since current treatments act essentially on the inflammatory process", says Dr. Xavier Montalban, head of the Neurology Department at Vall d'Hebron University Hospital, head of the Clinical Neuroimmunology research group at VHIR and director of Cemcat.

The results also highlight the effect of smoking and educational level on the disability caused by multiple sclerosis. Thus, it is observed that the educational level increases resistance to neurodegeneration, while smoking is related to the acceleration of disease progression.

In addition to the variant between DYSF-ZNF638, the results also show that the DNM3-PIGC variant could play a role in the progression of severe disease symptoms and in difficulty in walking, although the association is not as marked as in the case of the former. The researchers therefore emphasize the need for further research to learn more about the impact of these and other possible variants on disease progression.

The work has been possible thanks to the collaboration of more than 70 institutions from Europe, Australia, the United States and Canada that form part of two of the most relevant multiple sclerosis research consortia: the International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium.