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98 pcnt of genes that Vitamin D activates to reduce MS are also activated by Interferon -May 2013

25-Hydroxyvitamin D and MS Activity During Therapy with Interferon Beta-1b

CMSC Conference, May 30, 2013 Florida
Alberto Ascherio, MD , Harvard University, Boston, MA
Kassandra Munger, ScD , Harvard University, Boston, MA
Claire Simon, ScD , Harvard University, Boston, MA
Ludwig Kappos, MD , University Hospital, Basel Neurology, Basel, Switzerland, Basel, Switzerland
Chris H Polman, MD , VU Medical Center, Amsterdam, Netherlands
Mark Freedman, MD , University of Ottawa, Ottawa, ON, Canada
Hans-Peter Hartung, MD , Heinrich-Heine University, Dusseldorf, Germany, Dusseldorf, Germany
David Miller, MBChB, MD, FRCP , UCL Institute of Neurology, London, United Kingdom
Xavier Montalban, MD , Hospital Universitari Vall d’Hebron, Barcelona, Spain
Gilles Edan, MD , CHU-Hôpital Pontchaillou, Rennes, France
Frederik Barkhof, MD, PhD , VU Medical Center, Amsterdam, Netherlands
Rupert Sandbrink, MD , Bayer Pharma AG, Berlin, Germany
Karl Kochert, MD , Bayer Pharma AG, Berllin, Germany
Christoph Pohl, MD , Department of Neurology, University Hospital of Bonn, Berlin, Germany

Background: Recently, various studies have been dissecting possible beneficial effects of 25-hydroxyvitamin D (25OHD) in reducing disease burden and MRI detectable disease activity in multiple sclerosis (MS).

Objectives: We studied the impact of 25(OH)D levels under interferon beta-1b (IFNB-1b) treatment on global gene expression levels with respect to the activity of MS.

Methods: BENEFIT studied IFNB-1b in patients with a clinically isolated syndrome (CIS). Within the first 2 years of the study, contrast-enhanced cerebral MRI scans and 25(OH)D were obtained at the CIS and after 6, 12, and 24 months. In addition, gene expression profiles in peripheral blood mononuclear cells (PBMC) were determined using Affymetrix HGU 133 plus 2 arrays at the CIS and after 2/3, 12 and 24 months. The association of ~19,000 genes with enhancing lesions, with 25(OH)D, and with IFNB-1b treatment was modeled with negative binomial and Gaussian generalized linear models. Gene set enrichment analysis (GSEA) was performed to test the association of previously described gene sets relevant for the function of IFNB-1b and 25(OH)D with the number of enhancing MRI lesions. For naïve, threshold based gene-function classification, the Database for Annotation, Visualization and Integrated Discovery (DAVID ) v6.7 was used.

Results: Higher 25(OH)D levels (p=0.0013) and IFNB-1b treatment (p<0.0001) were significantly associated with a lower number of enhancing lesions. 63 genes were significantly associated (p<0.05) with 25(OH)D levels; all but one of them were also associated with IFNB-1b treatment, which was significantly associated with 770 genes. GSEA showed that 25(OH)D gene sets reflecting the impact of vitamin D receptor binding on respective target genes as well as some IFNB-1b response gene sets were highly significantly associated with enhancing lesions. IFNB-1b and 25(OH)D regulated similar genes and first-line immune regulatory processes as shown by DAVID-based gene-function classification.

Conclusions: The results show a beneficial role of 25(OH)D on MS activity. On a molecular level in PBMCs, the mechanistic explanation for this effect is a systemic gene regulation by 25(OH)D which is part of a larger systemic gene response to IFNB-1b therapy. Genes associated with either of the 2 are mainly steering immunological processes that impact on the inflammatory activity of MS.


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