Epub: Disanto et al. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet. 2012 May 16.
Both
genetic and environmental factors contribute to the aetiology of MS.
More than 50 genomic regions have been associated with MS susceptibility
and vitamin D status also influences the risk of this complex disease.
However, how these factors interact in disease causation is unclear. We
aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid (lymphocyte/white blood cell tumours) cell lines (LCLs), chromatin
states in LCLs and MS associated genomic regions. Using the Genomic
Hyperbrowser, we found that VDR binding regions overlapped with active
regulatory regions (active promoter (AP) and strong enhancer (SE)) in
LCLs more than expected by chance (45.3 fold enrichment for SE
(p<2.0e-05) and 63.41 fold enrichment for AP (p<2.0e-05)).
Approximately 77% of VDR regions were covered by either AP or SE
elements. The overlap between VDR binding and regulatory elements was
significantly greater in LCLs than in non-immune cells (p<2.0e-05).
VDR binding also occurred within MS regions more than expected by chance
(3.7 fold enrichment, p<2.0e-05). Furthermore, regions of joint
overlap SE-VDR and AP-VDR were even more enriched within MS regions and
near to several disease associated genes.These findings provide relevant
insights into how vitamin D influences the immune system and the risk
of MS through VDR interactions with chromatin state inside MS regions.
Furthermore, the data provides additional evidence for an important role
played by B cells in MS.
genetic and environmental factors contribute to the aetiology of MS.
More than 50 genomic regions have been associated with MS susceptibility
and vitamin D status also influences the risk of this complex disease.
However, how these factors interact in disease causation is unclear. We
aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid (lymphocyte/white blood cell tumours) cell lines (LCLs), chromatin
states in LCLs and MS associated genomic regions. Using the Genomic
Hyperbrowser, we found that VDR binding regions overlapped with active
regulatory regions (active promoter (AP) and strong enhancer (SE)) in
LCLs more than expected by chance (45.3 fold enrichment for SE
(p<2.0e-05) and 63.41 fold enrichment for AP (p<2.0e-05)).
Approximately 77% of VDR regions were covered by either AP or SE
elements. The overlap between VDR binding and regulatory elements was
significantly greater in LCLs than in non-immune cells (p<2.0e-05).
VDR binding also occurred within MS regions more than expected by chance
(3.7 fold enrichment, p<2.0e-05). Furthermore, regions of joint
overlap SE-VDR and AP-VDR were even more enriched within MS regions and
near to several disease associated genes.These findings provide relevant
insights into how vitamin D influences the immune system and the risk
of MS through VDR interactions with chromatin state inside MS regions.
Furthermore, the data provides additional evidence for an important role
played by B cells in MS.
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| Vitamin D receptor
“The evidence is overwhelming that vitamin D deficiency increases the risk of developing MS. The question is how? Vitamin D can act in the genome by binding to its own receptor called the vitamin D receptor or VDR. We have previously mapped out where in the genome the VDR binds. Here we are trying to understand the function of VDR binding. The majority of vitamin D binding sites are at gene regulatory sites; the probability of this happening by chance is extremely low- i.e. vitamin D is playing an active role in regulating genes. Secondly of the 60 or so genes associated to MS, we show hear that nearly 80% of them are regulated by vitamin D, again the probability of this being a chance finding is smaller than the chances of one of us winning the lottery. It seems clear that vitamin D influences the risk of getting MS through gene-environment interactions. So now the question is- for people at high risk of getting the disease (for example carrying all the risk genes) can we give them high dose vitamin D to prevent them from ever getting MS? I hope so.”
|
CoI: This work was done by some members of Team G
Ram, I waned to ask you about the comments Dr. Alasdair Coles made at MS Life in April about vitamin D.
In his brilliant lecture on immunology, Coles stated that although immune cells in the lab need high doses of vitamin D to have an affect, he does not think immune dcells in the human body need as higher levels to impact positively on the immune system. Although he does think that current government guidelines on the ammount of vit D are too low, he doesn't believe you need too high doses to make good.
Also, what are your thoughts on vit D2? Do you regard vit D2 as rubbish when compared to vit D3? I only ask because vit D2 is cheaper than vit D3 and more widely available.
I havent been able to watch Dr Coles talk. The player always stops a few minutes into the talk
Hi Anonymous 1,
I'm not sure what levels Dr Coles thinks are needed, but the evidence does suggest we need vitamin D levels close to 100nmol/L to illicit a good immune response. For example this study-http://www.ncbi.nlm.nih.gov/pubmed/21697250
In order to achieve vitamin D levels this high you would need to take supplements especially during the winter.
D2 is generally thought to be less biologically effective than D3. Have you seen this website?
http://www.vitamind3uk.com/
6 months supply of 5000IU tablets are about £15. Obviously there are other manufacturers out there but I am just highlighting this one as I know it is a reliable company.
Ram – once you get progressive MS, will taking vit D help? If it does help then how can it benefit progressive MSers?
I've got a similar question as the poster before. I take my VitD daily but would like to have the following clarified, please:
Does taking VitD actually help once you got the disease (RRMS)?
Any scientific data on reduced lesion activity, number of relapses etc?
Sorry if the answer to that can be found on the blog – I didn't find it, though.
Video stops after a few minutes..maybe a quality comtrol device:-)
Not from the little I saw!
Hi Anonymous 1,
I''m not sure how much Dr Coles thinks is enough, but there is definite evidence to suggest that vitamin D levels optimal for the immune system need to be greater than 80nmol/l.
In order to maintain our levels this high supplementation would be needed in the winter.
D3 is thought to be more biologically active form of vitamin D and the one to get if you can.
Anonymous 3,
Vitamin D without a doubt helps your bones, which is a big problem for PPMSers. As for whether it will help to protect MS, there is no 'gold standard' evidence of a trial showing that It helps PPMSers. However, my thoughts would be that everyone needs to be replete. It really can't harm in the doses being suggested and could do a lot of good.
Anonymous 4,
There have been trials performed in RRMSers, but sadly they weren't very well carried out. One trial showed a beneficial effect of vit D on relapses and MRI whereas another did not show any effect. We are waiting for the results of a bigger trial to provide a more definitive answer. However, with other proven benefits of vitamin D, again I think everyone needs to replete.