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=1x10-5. 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=5x10-7). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35/35 times (P=3x10-9).

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."