Genetic Studies

New Directions in MS Research: New Therapeutic Approaches

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There has been a growing body of evidence for the genetic component in MS. The studies on biomarkers have arisen as the result of this work, and a number of genes that are linked to the development of MS have been identified. This field of research saw a major break-through in August 2011, when the journal Nature published the results of the largest MS genetics study ever undertaken.65 A global collaboration of scientists identified 29 new genetic variants associated with MS, and confirmed 23 others that had been previously associated with the disease. The study confirmed that the immune system plays a major role in the development of MS: most of these genes are related to immune function, and more than one-third of them have previously been confirmed to be associated with other autoimmune diseases, such as Crohn’s disease and type 1 diabetes.

The study involved nearly 10,000 people with MS and more than 17,000 controls without MS, taking place in 15 countries. The research was carried out by approximately 250 investigators. The results are now to be confirmed and expanded in a second, large-scale study. The team found that a large number of these genes are related to T-cell function; they were mainly associated with T-cell activation and proliferation. This was particularly important because these are the cells believed to be the major mediators of the early immune attack on the brain and spinal cord in MS. Two of the genes are linked to Vitamin D, and low Vitamin D levels have already been implicated as a risk factor for developing MS. As noted earlier, more than one-third of the genes are associated with other autoimmune diseases such as Crohn’s disease and type 1 diabetes; MS is believed to be an autoimmune disease as well.

Investigation of MS prevention requires early identification and understanding of the incidence in a high-risk population. The Genes and Environment in Multiple Sclerosis (GEMS) project has a goal of early detection in first-degree relatives of MS patients. Data were presented in spring 2015. Each subject submitted saliva for targeted genotyping and completed questionnaires online to capture demographics and risk factors. For each subject, a weighted genetic and environmental risk score (GERS) was calculated. This score included 64 genetic variants, as well as gender, whether or not he or she had infectious mononucleosis, and if the person has a history of smoking.

By leveraging patient-advocacy groups and social media, the GEMS investigators were able to recruit more than 2,600 first-degree relatives of people with MS from across the United States. In an analysis of the initial 1,696 subjects (1,583 without symptoms and 113 with MS at enrollment), investigators found that 27 percent of the individuals with MS and 25 percent of the asymptomatic subjects have a history of infectious mononucleosis, both doubling that of the general population. This higher proportion of infectious mononucleosis in asymptomatic family members is not attributable to known MS-genetic susceptibility. MS subjects have a significant excess of current smokers than asymptomatic subjects. Four out of the initial 1,583 asymptomatic subjects developed MS after enrollment, providing an incidence estimate (123 cases per 100,000 first-degree relatives annually), which is significantly higher than the incidence of sporadic MS in the United States. The average follow-up duration of the study was two years.

The GEMS study highlights the role of electronic communication, e.g., using social media and web-based questionnaires, in rapid and large-scale subject recruitment of first-degree relatives. It also provides a first estimate of the incidence of MS among this high-risk population, critically informing the design of a prospective study of high-risk family members. Identification of patients at the highest risk for MS may lead to opportunities for intervention before the condition becomes clinically apparent.

These and other genetics studies do not as yet significantly improve our ability to provide genetic counseling to individuals concerned about their risk of developing MS. However, they should help researchers to better define the biological pathways that lead to the development of MS, and may allow us to design better treatments for early MS.

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