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The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells


Shahijanian, F and Parnell, GP and McKay, FC and Gatt, PN and Shojoei, M and O'Connor, KS and Schibeci, SD and Brilot, F and Liddle, C and Batten, M and Baxter, A and Kermode, A and Carroll, W and Butzkueven, H and Vucic, S and Wiley, J and Field, J and Tajouri, L and Griffiths, L and Barnett, M and Scott, R and Lechner-Scott, J and Moscato, P and Broadley, S and Slee, M and Kilpatrick, T and Taylor, B and Charlesworth, J and Brown, M and Mason, D and Stewart, GJ and Booth, DR, The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells, Human Molecular Genetics, 23, (6) pp. 1425-1434. ISSN 1460-2083 (2014) [Refereed Article]

Copyright Statement

Copyright 2013 the authors

DOI: doi:10.1093/hmg/ddt529


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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Taylor, B (Professor Bruce Taylor)
UTAS Author:Charlesworth, J (Dr Jac Charlesworth)
ID Code:88169
Year Published:2014 (online first 2013)
Web of Science® Times Cited:35
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-01-15
Last Modified:2021-01-04

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