title: Vitamin D receptor binding, chromatin states and association with multiple sclerosis.
abstract: Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. However, how these factors interact in disease causation is unclear. We aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid cell lines (LCLs), chromatin states in LCLs and MS-associated genomic regions. Using the Genomic Hyperbrowser, we found that VDR-binding regions overlapped with active regulatory regions [active promoter (AP) and strong enhancer (SE)] in LCLs more than expected by chance [45.3-fold enrichment for SE (P < 2.0e-05) and 63.41-fold enrichment for AP (P < 2.0e-05)]. Approximately 77% of VDR regions were covered by either AP or SE elements. The overlap between VDR binding and regulatory elements was significantly greater in LCLs than in non-immune cells (P < 2.0e-05). VDR binding also occurred within MS regions more than expected by chance (3.7-fold enrichment, P < 2.0e-05). Furthermore, regions of joint overlap SE-VDR and AP-VDR were even more enriched within MS regions and near to several disease-associated genes. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS regions. Furthermore, the data provide additional evidence for an important role played by B cells in MS. Further analyses in other immune cell types and functional studies are warranted to fully elucidate the role of vitamin D in the immune system.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Giulio
authors.initials: G
authors.lastname: Disanto
authors.forename: Geir Kjetil
authors.initials: GK
authors.lastname: Sandve
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Berlanga-Taylor
authors.forename: Giammario
authors.initials: G
authors.lastname: Ragnedda
authors.forename: Julia M
authors.initials: JM
authors.lastname: Morahan
authors.forename: Corey T
authors.initials: CT
authors.lastname: Watson
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: George C
authors.initials: GC
authors.lastname: Ebers
authors.forename: Sreeram V
authors.initials: SV
authors.lastname: Ramagopalan
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology; D020029:Base Pairing; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015894:Genome, Human; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D002843:Chromatin; D018167:Receptors, Calcitriol