Vitamin D insufficiency is a risk factor for a number of diseases and thus, is a growing concern worldwide, as approximately one billion people may be vitamin D deficient. However, the biological basis for vitamin D deficiency predisposing to disease is poorly understood. In a report published online in Genome Research, scientists have mapped the molecular interactions of the vitamin D receptor genome-wide, finding novel connections of vitamin D with genes related to autoimmune disease and cancer.
Vitamin D deficiency, resulting from either lack of sun exposure or poor dietary intake, is increasingly being recognized as a risk factor for a number of serious illnesses, and has been linked with autoimmune conditions such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Yet exactly how vitamin D is involved in disease is largely unknown. Researchers suspect that genetics could be contributing to the connection.
Vitamin D exerts its effects on genes through the vitamin D receptor (VDR), which binds to specific locations of the genome to influence gene expression. An international team of researchers from the United Kingdom and Canada have now mapped sites of VDR binding, information they can then use to identify disease-related genes that vitamin D might influence.
Employing a technique called ChIP-seq, Dr. Sreeram Ramagopalan, of the Wellcome Trust Centre for Human Genetics at Oxford University, and colleagues isolated fragments of genomic DNA bound to the VDR before and after treatment of cells with calcitriol, the active form of vitamin D, and then sequenced the DNA fragments. By mapping the sequences back to the genome, they identified more than 2,700 sites of VDR binding, a number that Ramagopalan noted “shows just how important vitamin D is to humans, and the wide variety of biological pathways that vitamin D plays a role in.”
In recent years, genome-wide association studies (GWAS) have uncovered numerous genomic regions harboring genetic variants that confer increased risk to disease. To identify potential genetic links between vitamin D and disease, the group analyzed known disease-associated regions of the genome looking for enrichment of VDR binding in these intervals.
They found that VDR binding is significantly enriched in genomic regions associated with several common autoimmune diseases, such as multiple sclerosis, type 1 diabetes, and Crohn’s disease. Importantly, the analysis revealed a novel role for vitamin D at several disease genes, information that will be crucial for future investigations. VDR binding was also enriched in regions associated with cancers such as leukemia and colorectal cancer, and even common traits such as tanning, height, and hair color.
Ramagopalan explained that their findings lend significant support to the hypothesis that vitamin D interacts with genes in the pathogenesis of these diseases, and underscores the serious risks of vitamin D deficiency, especially for individuals who may be genetically predisposed to be sensitive to insufficiency. “Considerations of vitamin D supplementation as a preventative measure for these diseases are strongly warranted,” Ramagopalan added.
Scientists from the University of Oxford (Oxford, UK), Barts and The London School of Medicine and Dentistry (London, UK), and Simon Fraser University (Burnaby, Canada) contributed to this study.
This work was supported by the Multiple Sclerosis Society of Canada Scientific Research Foundation, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Medical Research Council (UK), and the Wellcome Trust (UK).
About the article
The manuscript will be published online ahead of print on August 24, 2010. Its full citation is as follows: Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton S, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC. A ChIP-seq-defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res doi:10.1101/gr.107920.110.
Source: Cold Spring Harbor Laboratory Press