Vitamin D linked with genetic susceptibility to multiple sclerosis

6 February 2009

Multiple sclerosis (MS) is a complex neurological autoimmune disease caused by inflammatory damage of the myelin sheath that surrounds nerve fibres (demyelination). This damage results in impaired neurotransmission, and can lead to progressive disability. Both genetic and environmental factors are thought to play a significant effect in the pathogenesis of MS. The strongest genetic association has been identified for the HLA-DRB1 locus, which encodes a human leukocyte antigen (HLA) protein, part of the major histocompatibility complex (MHC) that is a key mediator of immune recognition; the DRB1*15 haplotype increases risk of MS by 3-fold.

Environmental factors are known to be important due to the striking geographical distribution of disease; MS affects predominantly temperate regions, with prevalence rates much higher in countries closer to the poles than the equator. For example, the paper cites a 5-fold difference in MS risk between Tasmania in the south and Queensland in the north of Australia. This has led to the suggestion that sunlight and vitamin D may play a key role in susceptibility to MS; vitamin D is a hormone synthesised in the skin, with additional (but less significant) dietary intake. A new paper in the open access journal PLoS Genetics reports on the findings from research intended to identify any links between vitamin D and HLA-DRB1 [Ramagopalan SV et al. (2009) PLoS Genet 5(2), doi:10.1371].

The researchers from the UK and Canada (two countries with particularly high disease prevalence) used computer programs to search for possible Vitamin-D responsive regulatory elements close to the HLA-DRB1, HLA-DQA1 and HLA-DQB1 genomic regions. Sequence analysis identified a single MHC vitamin D response element (VDRE) in the promoter region of HLA-DRB1. This putative VDRE sequence was sequenced in hundreds of individuals homozygous for the HLA-DRB1*15 MS risk allele, and found to be identical. However, sequencing in individuals homozygous for other HLA-DRB1 alleles revealed various sequence variations.

The authors next used molecular biological experiments to demonstrate that the VDRE specifically bound to vitamin D receptor in vitro, and that the HLA-DRB1*15 promoter sequence mediated vitamin D inducible gene expression. Deletion of the VDRE, or substitution of non–MS-associated HLA-DRB1 alleles removed this effect. Finally, the cell surface expression of the HLA-DRB1 protein subunit was shown to increase on the addition of vitamin D to HLA-DRB1*15 lymphoblastoid cells, but not to cells expressing other HLA-DRB1 alleles.

The conclusion of the paper is that vitamin D specifically interacts with the promoter region of HLA-DRB1*1501 to influence its expression, providing a functional link between observed genetic and environmental epidemiological data. They propose that dietary vitamin D supplementation at critical time periods may be important for disease prevention. Lead researcher Dr Sreeram Ramagopalan said that the study "implies that taking vitamin D supplements during pregnancy and the early years may reduce the risk of a child developing MS in later life" (see BBC news report), although it is likely that vitamin deficiency at these periods may influence risk to all kinds of disease.

Comment: The authors postulate that insufficient vitamin D in early childhood or before birth might affect expression of in HLA-DRB1*15 in the thymus, interfering with the normal process of thymic deletion (whereby autoreactive, ‘self’-recognising T-cells are removed from the immature immune system) and increasing the risk of autoimmunity and MS. The evidence thus far certainly supports a specific interaction with an influence on susceptibility to MS; however, there are other genetic and environmental factors that will play a role in the disease, and further research will be necessary to understand them better. Meanwhile, this latest finding may aid studies into the pathogenesis of MS.

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