Journal article
The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells
Human Molecular Genetics, Vol.23(6), pp.1425-1434
2014
Abstract
Genome-wide association studies have identified a linkage disequilibrium (LD) block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyzes the conversion of 25 vitamin D3 (VitD3) to 1,25VitD3. Fine-mapping analysis has failed to identify which of the 17 genes in this block is most associated with MS. We have previously used a functional approach to identify the causal gene. We showed that the expression of several genes in this block in whole blood is highly associated with the MS risk allele, but not CYP27B1. Here, we show that CYP27B1 is predominantly expressed in dendritic cells (DCs). Its expression in these cells is necessary for their response to VitD, which is known to upregulate pathways involved in generating a tolerogenic DC phenotype. Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by the genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolizes 1,25 VitD3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced VitD pathway gene upregulation in DC2s of carriers of the risk haplotype of CYP27B1 contributes to autoimmune diseases. These data support therapeutic approaches aimed at targeting VitD effects on DCs.
Details
- Title
- The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells
- Authors/Creators
- F. Shahijanian (Author/Creator) - Millennium InstituteG.P. Parnell (Author/Creator) - Millennium InstituteF.C. McKay (Author/Creator) - Millennium InstituteP.N. Gatt (Author/Creator) - Millennium InstituteM. Shojoei (Author/Creator) - The University of SydneyK.S. O'Connor (Author/Creator) - Millennium InstituteS.D. Schibeci (Author/Creator) - Millennium InstituteF. Brilot (Author/Creator) - Children's Hospital at WestmeadC. Liddle (Author/Creator) - Millennium InstituteM. Batten (Author/Creator) - Garvan Institute of Medical ResearchG.J. Stewart (Author/Creator) - Millennium InstituteD.R. Booth (Author/Creator) - Millennium InstituteA.G. Kermode (Author/Creator)
- Publication Details
- Human Molecular Genetics, Vol.23(6), pp.1425-1434
- Publisher
- Oxford University Press
- Identifiers
- 991005544248007891
- Copyright
- © The Author 2013
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.80 Bone Diseases
- 1.80.279 Vitamin D
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics