As a result, we could not perform meta-analysis for assessing the relationship in other ethnic groups.In summary, we found that the genetic variant rs703842 in CYP27B1 is associated with MS risk in Caucasians.
To compare vitamin D level-associated single-nucleotide polymorphisms (SNPs) in GC and CYP2R1, multiple sclerosis (MS) risk SNPs in CYP27B1, CYP24A1, and HLA-DRB1*1501, and adolescent exposure to environmental risk factors for hypovitaminosis D, with MS age at onset.
To investigate the influence of the multiple sclerosis (MS)-associated regulatory variant rs10877013 on the expression of genes involved in vitamin D activation (CYP27B1), vitamin D receptor (VDR), and vitamin D degradation (CYP24A1) under inflammatory environment or vitamin D.
Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s.
Sequencing CYP27B1failed to identify mutations known to cause loss of enzymatic activity, however genotyping of p.R389H in cases and controls identified the mutation in one multi-incident family (allele frequency=0.03%) in which the p.R389H mutation segregates with disease in five family members diagnosed with MS, thus providing additional support for CYP27B1p.R389H in the pathogenicity of MS.
Increased VDR expression in MS NAWM and inflammatory cytokine-induced amplified expression of VDR and CYP27B1 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions.
The demonstration that rare variants in CYP27B1, which encodes the enzyme that converts vitamin D to its active form, are strongly associated with MS risk supports a causal role of vitamin D deficiency as a risk factor for MS.
Further genotyping in >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)).
The 'C' allele of CYP27B1rs703842 was inversely associated with MS risk; this association appeared stronger among HLA-DR15 negative (OR = 0.79, 95% CI: 0.69, 0.90) compared to HLA-DR15 positive individuals (OR = 0.91, 95% CI: 0.80, 1.04).
Seventy-one SNPs, across four genes [vitamin D receptor (VDR), 1-alpha-hydroxylase (CYP27B1) enzyme, vitamin D binding protein (DBP), 24-hydroxylase (CYP24)], were genotyped and tested for association with MS susceptibility using TDT in PLINK.
We have identified 3 patients with this disease who later developed MS. We propose that VDDR I and possibly other hereditary rickets mutations that influence vitamin D metabolism could be risk factors for this disease.
We 1) examined the association of serum 25-hydroxy-vitaminD [25(OH)D] concentrations and MS status and 2) assessed the genetic contribution to serum 25(OH)D concentrations and tested for its association with genetic variants in 2 candidate genes [vitamin D receptor and 1-alpha-hydroxylase (CYP27B1)].