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Novel Genetics Study by National MS Society-Funded Team Begins to Map Out Disease Process of MS and similar diseases

October 29, 2014

Researchers have developed a new approach to understand how subtle changes in genes may lead to the risk of developing multiple sclerosis and other immune diseases. The study, by Drs. David Hafler (Yale University), Bradley Bernstein (MIT and Harvard University) and colleagues, maps out a strategy for tracing the influence of genes on cell activity, promising new insights for interrupting the MS disease process. The team created a sophisticated mathematical model that they applied to other immune-mediated diseases as well. The study, supported by the National MS Society, National Institutes of Health and other funders, was published in the journal Nature (advanced online publication, October 29, 2014).

Background: Research shows that MS occurs in individuals and in families whose genes make them susceptible to developing the disease, and that many genes contribute to MS susceptibility. In addition, individuals who are genetically at risk must also encounter triggering factors in the environment to actually develop MS. Pinpointing the exact location of these “MS genes” could help determine who is at risk for developing the disease, and may provide clues to better treatments and ending MS forever by prevention.

With early seed funding from a National MS Society Collaborative MS Research Center Award, researchers from around the world joined forces to create the International MS Genetics Consortium. Its work has already sped the search for MS genes exponentially, identifying over 100 genetic changes that are associated with MS risk. Understanding how these changes result in diseases such as MS continues to be puzzling.

The Study:  Interpreting the genetic variations identified by large scale genome studies remains a challenge. This team addressed that challenge, developing and testing a sophisticated mathematical model. First, they collected data from 39 large genetic screens (genome-wide association studies or GWAS) performed on different diseases. This effort highlighted a large cluster of genes shared by immune-mediated diseases, such as MS. Then, they used their model to analyze 21 autoimmune diseases, and were able to link broad regions identified in the GWAS to nearly 5,000 unique DNA variations in the genome, which were therefore considered candidates to be actual causes of the elevated genetic risk.

The group followed up by mapping these variations to the activity of 56 different cell types and confirmed that the variations were found near “master regulators” of gene functions, particularly genes involved in immune function. The results are an important step in connecting genetic variations linked to disease risk to the actual function of the genes. For MS, the study confirms a primary role for immune T cells, and for protein complexes such as nuclear factor kappa-B that control the “transcription” of DNA (a process that results in a change of cell function).

The researchers note that many of the gene variations – in MS and other immune diseases – occur in areas of the genome that seem important for controlling gene activity but that cannot yet be explained by existing models about how this activity is regulated. Although this points to the need for more research, which is currently underway, the strategy used by these investigators offers a roadmap for tracing the influence of genes on cell activity and promises new insights for interrupting the MS disease process and ultimately preventing MS.

Read more about the search for MS susceptibility genes.

About Multiple Sclerosis

Multiple sclerosis is an unpredictable, often disabling disease of the central nervous system. Symptoms range from numbness and tingling to blindness and paralysis, and there is currently no cure for MS. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are leading to better understanding and moving us closer to a world free of MS. An estimated 1 million people live with MS in the United States. Most people with MS are diagnosed between the ages of 20 and 50, and it affects women three times more than men.


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