Munger, KassandraKöchert, KarlSimon, Kelly CKappos, LudwigPolman, Chris HFreedman, Mark SHartung, Hans PMiller, David HMontalbán, XavierEdan, GillesBarkhof, FrederikPleimes, DirkSandbrink, RupertAscherio, AlbertoPohl, Christoph2014-11-032014Munger, K. L., K. Köchert, K. C. Simon, L. Kappos, C. H. Polman, M. S. Freedman, H. P. Hartung, et al. 2014. “Molecular mechanism underlying the impact of vitamin D on disease activity of MS.” Annals of Clinical and Translational Neurology 1 (8): 605-617. doi:10.1002/acn3.91. http://dx.doi.org/10.1002/acn3.91.2328-9503http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347476Objective: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D. Methods: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs). Results: The number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b. Interpretation Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.en-USJournal Article2014-11-0310.1002/acn3.91