Rare variants in vitamin D gene associated with MS

Ramagopalan et al. Rare variants in the CYP27B1 gene associated with multiple sclerosis. Ann Neurol 2011.Epub.

Objective: MS is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering.

Methods: We performed whole exome sequencing to further understand the heightened prevalence of MS in these families.

Results:  43 individuals with MS (one from each family) were sequenced looking for rare variants in candidate MS susceptibility genes. On average over 58000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in one individual. Homozygosity (two copies of the gene) for this mutation results in vitamin D dependent rickets I (VDDR1), while heterozygosity (one copy of the gene) results in lower calcitriol or vD levels. This variant showed significant heterozygous association in 3046 parent-affected child trios, P=1×10-5. Further genotyping in over 12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval 2.3-9.4, P=5×10-7). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35/35 times (P=3×10-9).

Interpretation: A causative role for CYP27B1 in MS is supported, indeed the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D activating 1-alpha hydroxylase enzyme and thus a role for vitamin D in MS pathogenesis is strongly implicated. 

“A tour de force in functional genomics. Who can now argue against the claim that vD is central to the pathogenesis of MS? All we need to find out is when does vD act – in utero, childhood, adolescence or adulthood – and what dose is required?”

“I think it acts at all ages and the dose of vitamin D we require is physiological and high enough to raise our blood levels to what is found in people living traditional lifestyles in equatorial Africa, where our ancestor arose. I always wanted practice evolutionary medicine; this is my time.”

7 thoughts on “Rare variants in vitamin D gene associated with MS”

  1. What does this mean for your EBV theory?If Vit D deficiency is the problem why do chemo agents have a positive effect?Why don't all ginger people get M?Not sure this is such a strong cause as you suggest.

  2. Re: "What does this mean for your EBV theory? If Vit D deficiency is the problem why do chemo agents have a positive effect? Why don't all ginger people get M? Not sure this is such a strong cause as you suggest."vD is critical for immune functioning. It may set the stage for autoimmune disease and for EBV to act. We are working on several fronts to try and tie up EBV and vD; too early to discuss. Prof. George Ebers believes if maintain our vD levels at "African" levels we will reduce MS incidence to that what is found in Africa; potentially an 85% reduction in risk. If you have MS and have children or siblings would you prepared to take the risk of not taking vD? An interesting thought.We have a moral obligation to act on knowledge, which is why we are trying to get a primary prevention study off the ground.

  3. You've gone native – too much contact with Prof Ebers.EBV is the most likely cause of the MS outbreaks which have been seen. Controlling EBV infected B cells has a big effect on the disease.Leave Prof E and Ram to the sunshine stuff (too many neuros spoil the broth!). You are Mr EBV and the nobel prize for medicine awaits you when you can show this and how it can be controlled. Your destiny is in your own hands – don't be lured by the dark side. Good luck.

  4. I disagree with previous poster – you're being lured by the 'sunlight' side! yes it is only an attempt at a joke 🙂

  5. Re: "You've gone native – too much contact with Prof Ebers."Professor Livingstone I presume? Spelt with a capital H?Causation theory states that you have to explain everything; so we can't focus on EBV only. There must be a link between the two. Please watch this space.

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