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Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele  HLA-DRB1*15∶01 , suggesting that with low vitamin D availability VDREs are incapable of inducing  *15∶01  expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated  DRB1 *04∶05 ,  *03∶01 , * 13∶01  and  *15∶01  and non-MS-associated  *16∶01 ,  *01 ,  *11 ,  *07∶01  alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the  DRB1  promoter region revealed a homozygous canonical VDRE in all  *15∶01, *16∶01, *11  and in 45/73  *03∶01  and in heterozygous state in 28/73  *03∶01  and all  *01  alleles. A new mutated homozygous VDRE was found in all  *13∶03 ,  *04∶05  and  *07∶01  alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of  DRB1  gene expression using an  in vitro  transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the  *04∶05  and  *03∶01  alleles carrying the new mutated VDRE, while the  *16∶01  and  *03∶01  alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of  VDR  to bind the mutant VDRE in the  DRB1  promoter was evaluated by EMSA. Efficient binding of  VDR  to the VDRE sequence found in the  *16∶01  and in the  *15∶01  allele reduced electrophoretic mobility when either an anti- VDR  or an anti- RXR  monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the  DRB1  gene in susceptibility to MS carried by  DRB1*  alleles in Sardinian patients.

Vitamin D Responsive Elements within the HLA-DRB1 Promoter Region in Sardinian Multiple Sclerosis Associated Alleles