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Dr. Philip De Jager - Results of the international MS genetics consortium
Dr. Philip De Jager, Brigham and Women’s Hospital, Boston, Massachusetts, USA, is interviewed on the results of the international MS genetics consortium, that has been able to relate many genetic variants to MS susceptibility.
The consortium presented the initial results of meta-analysis of genome-wide association scans performed in the past 5 years. The full study is to be completed in 2014. Currently, 207 variants have been identified with a robust association with MS susceptibility. More specifically, 110 variants related to immune function were reported to be associated with MS. These were seen to be involved in lymphocyte activation, co-stimulation, and fundamental signaling pathways such as the NFkB pathway. The discoveries are and will be validated through in vitro molecular studies, showing the importance of variant functions in specific molecular pathways, and using cellular studies. Common variants can be studied in cells from healthy subjects and MS patients, looking at e.g. RNA expression levels of the affected genes or downstream molecules in the same signaling pathways. Such experiments may also yield insights in how several variants combine to yield a certain phenotype. One example is the work on TNFα receptor 1 (TNFαR1) variant studies. A particular variant affects the probability to form a truncated isoform. Upon stimulation with TNFα, cells with the variant show an exaggerated response to TNFα. Interestingly, probably also another, unidentified (potentially environmental) factor can further exaggerate this response. Gender is the biggest MS risk factor, but no particular sex-specific variance has been indicated thus far. Ethnic differences have been studied, but it is hard to exclude environmental influences in the studies. Efforts are being made to improve this. Thus far, most variants found in the European population have also been detected in the African-American population. As variants found thus far are risk alleles and no alleles predicting disease course, the usefulness for true personalized medicine is still limited. That said, genetics will never be enough on its own merit for predictive medicine, but is useful in combination with other data. The risk alleles can be useful to assist the management of high risk individuals, e.g. not-yet affected family members of MS patients. Currently work is being done to design an algorithm for predicting risks within families using genetic and environmental factors.
As clinician, Philip De Jager is interested in developing useful tools for the clinic, understanding molecular events connecting disease to risk factors, and to expand the genetic quest to identify alleles that help to predict the MS disease course.