title: Molecular mechanism underlying the impact of vitamin D on disease activity of MS.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Harvard School of Public Health Boston, Massachusetts.
authors.forename: Kassandra L
authors.initials: KL
authors.lastname: Munger
authors.affiliation: Bayer HealthCare Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Köchert
authors.affiliation: Harvard School of Public Health Boston, Massachusetts.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Simon
authors.affiliation: University Hospital Basel Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.affiliation: Ottawa Hospital Research Institute Ottawa, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: Heinrich-Heine Universität Düsseldorf, Germany.
authors.forename: Hans P
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: UCL Institute of Neurology London, United Kingdom.
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.affiliation: Hospital Universitari Vall d'Hebron Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalbán
authors.affiliation: CHU-Hôpital Pontchaillou Rennes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Edan
authors.affiliation: VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Bayer HealthCare Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Pleimes
authors.affiliation: Bayer HealthCare Berlin, Germany ; Heinrich-Heine Universität Düsseldorf, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Sandbrink
authors.affiliation: Harvard School of Public Health Boston, Massachusetts.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ascherio
authors.affiliation: Bayer HealthCare Berlin, Germany ; Department of Neurology, University Hospital of Bonn Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Pohl