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, Baxter, Alan, Kermode, Allan, Carrol, William, Butzkueven, Helmut, Vucic, Steve, Wiley, James, Field, Judith, Tajouri, Lotti, Griffiths, Lyn, Barnett, Michael, Scott, Rodney, Lechner-Scott, Jeannette, Moscato, Pablo, Broadley, Simon, Slee, Mark, Kilpatrick, Trevor, Taylor, Bruce, Charlesworth, Jac, Brown, Matt, Mason, Deborah, Graeme, Stewart J., and Booth, David R. (2014) 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.

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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.

Item ID: 33477
Item Type: Article (Refereed Research - C1)
ISSN: 1460-2083
Funders: National Health and Medical Research Council of Australia (NHMRC), Multiple Sclerosis Research Australia, Hunt Family
Projects and Grants: NHMRC Project Grant 1049936, NHMRC Project Grant 633275, Hunt Family MS Senior Research Fellowship
Date Deposited: 10 Jun 2014 05:29
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110703 Autoimmunity @ 75%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 25%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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