title: Vitamin D receptor gene is epigenetically altered and transcriptionally up-regulated in multiple sclerosis.
abstract: OBJECTIVE
  Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR) gene to identify genomic regulatory elements relevant to MS pathogenesis.
  
  
  METHODS
  Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls.
  
  
  RESULTS
  An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2%) compared to controls (18.75%, 9.5%), p-value<0.05. Moreover, a 6.5-fold increase in VDR mRNA levels was found in RRMS patients compared to controls (p-value<0.001).
  
  
  CONCLUSIONS
  An alternative promoter of the VDR gene shows altered DNA methylation levels in patients with multiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis.
authors.affiliation: Multiple Sclerosis Unit, Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ayuso
authors.affiliation: Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Patricia
authors.identifier: http://orcid.org/0000-0002-1827-1779
authors.initials: P
authors.lastname: Aznar
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed- Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Soriano
authors.affiliation: Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Olaskoaga
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed- Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain.
authors.forename: Miren
authors.initials: M
authors.lastname: Roldán
authors.affiliation: Multiple Sclerosis Unit, Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Otano
authors.affiliation: Multiple Sclerosis Unit, Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Iratxe
authors.initials: I
authors.lastname: Ajuria
authors.affiliation: Multiple Sclerosis Unit, Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Soriano
authors.affiliation: Multiple Sclerosis Unit, Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lacruz
authors.affiliation: Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain.|Neuroepigenetics Laboratory, Navarrabiomed- Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain.
authors.forename: Maite
authors.identifier: http://orcid.org/0000-0002-4179-5781
authors.initials: M
authors.lastname: Mendioroz
mesh_terms: D000328:Adult; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D015854:Up-Regulation; D014807:Vitamin D / Q000097:blood; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014807:Vitamin D