Investigations of vitamin D as a determinant of multiple sclerosis risk and of the metabolome of disease progression

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Multiple sclerosis (MS) is a serious chronic disease of the central nervous system that commonly affects young adults and can lead to severe disability. Although the etiology of MS is not entirely understood, important risk factors have been identified. Vitamin D deficiency is among the modifiable environmental factors that have most consistently been associated with an increased MS risk, based on strong evidence from large cohort and Mendelian Randomization studies. However, crucial aspects of its involvement remain to be resolved. Previous findings suggest that adequate vitamin D levels may be especially important in early life, presumably during adolescence. Whether vitamin D elevation during adulthood could prevent MS or would come too late, remains to be resolved. Further, according to preliminary experimental evidence, vitamin D deficiency might be a stronger risk factor among women, but this has not been assessed in humans. Moreover, more information is needed on the specific vitamin D level associated with a risk increase and whether this cutoff differs by sex and ethnicity. This knowledge is necessary to inform recommendations for primary preventive interventions and will need to come from well-designed prospective epidemiologic investigations, as clinical trials on the effect of vitamin D for primary prevention of MS are unlikely to be conducted due to ethical reservations and practical challenges.Further, once diagnosed, MS patients face a disease with a highly variable disease course that is difficult to predict, which in itself is a burdensome aspect of the condition. Predictors of a severe disease course and long-term progression are urgently needed to inform patients and treating physicians. Profiles of blood metabolites reflect interactions between genetic and environmental factors, and may thus capture components that affect the disease course. Preliminary evidence from small studies on specific metabolites is promising but larger prospective in-depth discovery studies are needed to identify a metabolic profile and early biomarkers of severe disease and long-term progression.The aims of the proposed research are therefore twofold:1) To investigate the association between vitamin D and MS risk in detail considering differences by age, sex, and ethnicity, using repeated blood samples from a large prospective US cohort.2) To investigate the metabolic plasma profile of MS patients and identify early predictors of long-term disability and disease progression, using blood samples of participants of a clinical trial with observational 11-year follow-up (BENEFIT study).These studies will be conducted within the research group of Prof. Ascherio at the Department of Nutrition at the Harvard T.H. Chan School of Public Health that has access to worldwide unique cohorts, suitable to investigate these research questions. The findings might have important translational implications for prevention and treatment of multiple sclerosis.