Research: vitamin D and the main MS genetic risk factor

Epub: Nolan et al. Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk.  Neurology. 2012 Jul 11.

"This research is what I call hard-core functional genomics and supports other studies already published. All genes have an area upstream of the protein coding reading that controls whether they are switched ON or OFF. The area that controls on the ON function is called the promoter. The major group of genes that control the risk of MS, called the HLA-DRB1*1501, has a a vitamin D ON switch. This switch is not an all or nothing switch but acts as a dimmer switch. If vitamin D levels are high it switches this gene ON very bright and if vitamin D levels are low this switch is set on ON low or dim. Interestingly other genes in this family don't have a vitamin D switch and are therefore are unaffected by vitamin D levels and some of these vitamin D non-responsive genes protect you from MS. What is important is that this family of genes that are linked to MS risk play a vital role in controlling the immune system and have to be switched on brightly early in life to educate the developing immune system. We believe low levels of vitamin D in utero or in early in life, results in the MS at-risk gene been set on DIM; as a result the immune system is wrongly educated and this then puts you at risk of MS when you get older. This is the main reason why we believe that vitamin D supplementation as a preventative strategy for MS needs to be given early in life, possibly in utero. If you are under my care I stress this, which is why I always talk about planning your pregnancies, getting your children onto vD supplements and to educate your siblings and their children. I wish public health officials would do this instead - I becoming an accidental public health doctor. Don't worry I like doing it; in fact if I knew what I know now when I was in medical school, I would almost certainly have specialised in public health and health economics."

OBJECTIVE: The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk.

METHODS: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls.

RESULTS: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10(-12)) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10(-18)).

CONCLUSIONS: HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D-dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the "nonresponsive" VDRE motif were associated with significantly reduced risk of MS.