Multiple sclerosis, vitamin D, and HLA-DRB1*15
NEUROLOGY 2010;74:1905-1910
Lahiru Handunnetthi, MSc, Sreeram V. Ramagopalan, DPhil and George C. Ebers, MD, FMedSci
From the Wellcome Trust Centre for Human Genetics and the Department of Clinical Neurology, University of Oxford, Oxford, UK.
Address correspondence and reprint requests to Professor George C. Ebers, University Department of Clinical Neurology, Level 3, West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK george.ebers at clneuro.ox.ac.uk
Background: Multiple sclerosis (MS) has a remarkable geographic distribution inversely paralleling that of regional ultraviolet radiation, supporting the hypothesis that vitamin D plays a central role in the disease etiology. The major histocompatibility complex exerts the largest genetic contribution to MS susceptibility, but much risk remains unexplained and direct gene-environment interaction is a strong candidate for this additional risk. Such interactions may hold the key for disease prevention.
Recent developments: Several recent studies strengthen the candidacy of vitamin D as a key player in the causal cascade to MS. This includes a newly identified gene-environment interaction between vitamin D and the main MS-linked HLA-DRB1*1501 allele and evidence showing that vitamin D levels are significantly lower in patients with MS as compared to controls. Also, a recent study in twins with MS supports the notion that vitamin D levels are under regulation by genetic variation in the 1{alpha}-hydroxylase and vitamin D receptor genes, perhaps pointing to their importance in the disease pathogenesis.
Conclusions: These findings have important practical implications for studies of disease mechanisms and prevention. Missing genetic risk may partly be explained by gene-environment interactions. More practically important is that these observations highlight a pressing need to determine if vitamin D supplementation can reduce the risk of multiple sclerosis (MS). However, the timing of action and the tissues in which this interaction takes place are not clear and future studies in prospective cohorts and animal models will be essential for deciphering the role of vitamin D in MS.
Abbreviations: MHC = major histocompatibility complex; MS = multiple sclerosis; VDR = vitamin D receptor; VDRE = vitamin D response element.
Received October 2, 2009. Accepted in final form March 11, 2010.
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