Research: vitamin D and MS risk genes

R
Cocco E, et al. Vitamin D Responsive Elements within the HLA-DRB1 Promoter Region in Sardinian Multiple Sclerosis Associated Alleles. PLoS One. 2012;7(7):e41678. 


“This is hardcore science and looks at the interaction of vD with the major genetic locus associated with MS. This study casts some doubt on the role of vD in controlling this family of genes in the Sardinian population. Clearly more work needs to be done on how vD interact with genetic risk factors. This needs to be explained as to prove causation you have to explain everything and I mean everything; vD, genetics, EBV, smoking, migration, changing sex ratios, etc.”

 
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. This study tested 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 MSers and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous 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.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

1 comment

  • Just a few ideas:

    Maybe it's due to racial differences – Sardinians used to be a part of Byzantium and so I guess exchange of different genes occurred
    – in more modern times Sardinia used to have lots of exposure to foreigners via Nato base so this would be in favour of viral theories
    – or it's linked to heavy industralisation which in such a small place must have caused lots of pollution

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