Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

Abstract

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention.

Vitamin D supplementation differentially affects seasonal multiple sclerosis disease activity

“…Concordantly, several studies have found an inverse correlation between serum 25(OH)D concentration and disease activity in MS patients (Brola et al, 2016;Pierrot-Deseilligny, Rivaud-Péchoux, Clerson, de Paz, & Souberbielle, 2012;Rotstein et al, 2015;Simpson et al, 2010). These findings are supported by genetic data showing that the MS susceptibility gene HLA-DRB1*1501 is regulated by a VDdependent promotor (Ramagopalan et al, 2009). …”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…117 We have recently shown how genetic variation defines a functional VDRE in the proximal promoter of HLA-DRB1 ( Figure 5). 118 Strikingly, this VDRE showed haplotype-specific differences, being highly conserved in the major MS-associated haplotype HLA-DRB1*1501 in Northern European populations, but disrupted to varying degrees in non-disease associated haplotypes. Functional assays showed that this VDRE can influence gene expression, conferring vitamin D sensitivity to the HLA-DRB1*1501 haplotype.…”

Multiple sclerosis genetics

“…Multiple studies showed that 25-OH vitamin D levels are lower in MS cases compared to controls in both European-descended and African American populations (Munger et al, 2006;Islam et al, 2007;Gelfand et al, 2011;Ramagopalan et al, 2011b (Ramagopalan et al, 2009). Vitamin D receptor-binding elements have been identified in the majority of MS-associated genes, implying that expression of many of these genes could also be controlled by vitamin D (Ramagopalan et al, 2010).…”