Genetic Studies

New Directions in MS Research: New Therapeutic Approaches

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A growing body of evidence has been found 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 breakthrough in August 2011, when the journal Nature published the results of the largest MS genetics study ever undertaken.68 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.

Since that point in time, larger studies have greatly expanded upon that work, including69 the most recent large-scale study of genetics and MS in which 47,351 persons with MS and 68,284 healthy controls were included. Researchers were able to identify more than 200 important genetic variants associated with MS. Most genes again were related to the immune system. Interestingly, study investigators also identified new genetic variants located on the X chromosome, which they hypothesized might in part explain the increased risk in MS for a woman compared to a man. 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 individuals with MS. Initial 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, including the subject with the highest genetic risk score, 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.

In a follow-up study published in early 2017, investigators studied women in the highest70 and lowest genetic risk categories. They reported that in 8 percent of study participants (four in the high-risk category and one in the lower-risk category) had MRIs that showed lesions consistent with MS. Surprisingly, researchers also found that they were significantly more likely to be able to detect subtle decreases in vibration sense in the big toe in subjects with a higher genetic score when compared to those with a lower genetic score.

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 people at the highest risk for MS may one day allow for an intervention before a person has any symptoms.

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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