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.

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.

Figure 1

Flowchart of available data and size of data partitions used in the different analyses.

Figure 2

IFNB-1b and 25(OH)D-regulated genes are additionally associated with regulating the count of Gd-enhancing lesions. (A) Venn diagram depicting the overlap between genes that are associated with Gd-enhancing lesions, 25(OH)D or IFNB-1b. (B) Genes whose induction is associated with a reduction of Gd lesion count and which are upregulated through 25(OH)D and IFNB-1b. (C) Genes whose induction is associated with a reduction of Gd lesion count and which are downregulated through 25(OH)D and IFNB-1b. (D) Genes whose induction is associated with an increase of Gd lesion count and which are upregulated through 25(OH)D and IFNB-1b. (E) Genes whose induction is associated with an increase in Gd lesion count and which are downregulated through 25(OH)D and IFNB-1b. IFNB-1b, interferon beta-1b; 25(OH)D, 25-hydroxyvitamin D.

Figure 3

25(OH)D and MS activity gene interaction networks. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to visualize knowledge-based connectivity of genes being associated with 25(OH)D levels (A) or Gd-enhancing lesion count (B). Thickness of lines is proportional to the probability of a true interaction of any pair of genes. 25(OH)D, 25-hydroxyvitamin D; MS, multiple sclerosis.