Abstract
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.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system
On the basis of these data, we propose that in Sardinian MS population Vitamin D response elements (VDREs) in the promoter region of the DRB1 gene do not influence susceptibility to the disease
Vitamin D has been proposed to have a key role in the risk of developing MS [30]
Summary
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system. A complex multi-locus and multi-allelic disease association with the main genetic effects encoded by variation at the HLA class II loci DRB1 and DQB1 has been found in Sardinia. The main predisposing haplotype in Northern European populations, (DR2) DRB1*15:01-DQB1*06:02 [15], very rare in the Sardinian population, is still significantly positively associated with MS [13,14]. The DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype, which has a high frequency in other ethnic groups, is rare in Sardinia (haplotype frequency 1.5%) [16]. Sardinians, in contrast to other Caucasian populations, have virtually only one DR4-DQB1*03:01 haplotype in which the DQ-a chain is encoded by the DQA1*05:01 gene (i.e., the DRB1*04:05-DQA1*05:01-DQB1*03:01 haplotype) [16]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.