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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.

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