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

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...

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Bibliographic Details
Published in:PloS one Vol. 7; no. 7; p. e41678
Main Authors: Cocco, Eleonora, Meloni, Alessandra, Murru, Maria Rita, Corongiu, Daniela, Tranquilli, Stefania, Fadda, Elisabetta, Murru, Raffaele, Schirru, Lucia, Secci, Maria Antonietta, Costa, Gianna, Asunis, Isadora, Cuccu, Stefania, Fenu, Giuseppe, Lorefice, Lorena, Carboni, Nicola, Mura, Gioia, Rosatelli, Maria Cristina, Marrosu, Maria Giovanna
Format: Journal Article
Language:English
Published: United States Public Library of Science 25.07.2012
Public Library of Science (PLoS)
Subjects:
Adult
Alleles
Autoimmune diseases
Autoimmunity
Base Sequence
Biology
Case-Control Studies
Clonal deletion
Computational Biology
Diabetes
Disease susceptibility
Drb1 protein
Electrophoretic mobility
Female
Gene expression
Genetic Predisposition to Disease - genetics
Genomes
Haplotypes
Histocompatibility antigen HLA
HLA antigens
HLA-DRB1 Chains - genetics
Humans
Insulin-like growth factors
Italy
Lymphocytes T
Male
Medicine
Metabolites
Molecular Sequence Data
Monoclonal antibodies
Multiple sclerosis
Multiple Sclerosis - genetics
Patients
Population
Proteins
Radiation effects
Receptors, Calcitriol - metabolism
Regulatory sequences
Retinoid X receptors
Sequence Analysis, DNA
Solar radiation
T cells
Thymus
Transcription
Transcriptional Activation - genetics
Vitamin D
Vitamin D receptors
Vitamin D Response Element - genetics
Italy
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary: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.
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Conceived and designed the experiments: MGM EC MRM AM MCR. Performed the experiments: AM DC ST EF RM LS MAS GC SC IA. Analyzed the data: MGM EC MRM AM MCR GF LL NC GM. Contributed reagents/materials/analysis tools: AM DC ST EF RM LS MAS GC SC IA. Wrote the paper: MGM EC AM MRM MCR. Recruited the patients and samples: GF LL NC GM.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0041678