6 February 2009
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.