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

Shahijanian, Fernando, Parnell, Grant P., Mckay, Fiona C., Gatt, Prudence N., Shojoei, Maryam, O'Connor, Kate S., Schibeci, Stephen D, Brilot, Fabienne, Liddle, Christopher, Batten, Marcel, Stewart, Graeme J., Booth, David R., ANZgene Multiple Sclerosis Genetics Consortium and Brown, Matt (2014) The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells. Human Molecular Genetics, 23 6: 1425-1434. doi:10.1093/hmg/ddt529


Author Shahijanian, Fernando
Parnell, Grant P.
Mckay, Fiona C.
Gatt, Prudence N.
Shojoei, Maryam
O'Connor, Kate S.
Schibeci, Stephen D
Brilot, Fabienne
Liddle, Christopher
Batten, Marcel
Stewart, Graeme J.
Booth, David R.
ANZgene Multiple Sclerosis Genetics Consortium
Brown, Matt
Total Author Count Override 13
Title The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
1460-2083
Publication date 2014-03-15
Year available 2013
Sub-type Article (original research)
DOI 10.1093/hmg/ddt529
Open Access Status
Volume 23
Issue 6
Start page 1425
End page 1434
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 24 october 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
 
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Created: Fri, 14 Mar 2014, 12:29:07 EST by Kylie Hengst on behalf of UQ Diamantina Institute