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

ANZgene Multiple Sclerosis Genetics Consortium

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1425-1434
Number of pages10
JournalHuman Molecular Genetics
Volume23
Issue number6
DOIs
Publication statusPublished - 24 Oct 2014

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25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Dendritic Cells
Autoimmune Diseases
Multiple Sclerosis
Cholecalciferol
Genes
Linkage Disequilibrium
Up-Regulation
Alleles
Chromosomes, Human, Pair 12
Genome-Wide Association Study
Type 1 Diabetes Mellitus
Haplotypes
Genotype
Phenotype
Gene Expression

Cite this

@article{e20f186220934509a6b8eadc7fce5e06,
title = "The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells",
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.",
author = "{ANZgene Multiple Sclerosis Genetics Consortium} and Fernando Shahijanian and Parnell, {Grant P.} and Mckay, {Fiona C.} and Gatt, {Prudence N.} and Maryam Shojoei and O'Connor, {Kate S.} and Schibeci, {Stephen D.} and Fabienne Brilot and Christopher Liddle and Marcel Batten and Stewart, {Graeme J.} and David Booth and Alan Baxter and Allan Kermode and William Carroll and Helmut Butzkueven and David Booth and Graeme Stewart and Steve Vucic and James Wiley and Judith Field and Lotti Tajouri and Lyn Griffiths and Michael Barnett and Rodney Scott and Jeannette Lechner-Scott and Pablo Moscato and Simon Broadley and Mark Slee and Trevor Kilpatrick and Bruce Taylor and Jac Charlesworth and Matt Brown and Deborah Mason",
year = "2014",
month = "10",
day = "24",
doi = "10.1093/hmg/ddt529",
language = "English",
volume = "23",
pages = "1425--1434",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
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The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells. / ANZgene Multiple Sclerosis Genetics Consortium.

In: Human Molecular Genetics, Vol. 23, No. 6, 24.10.2014, p. 1425-1434.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells

AU - ANZgene Multiple Sclerosis Genetics Consortium

AU - Shahijanian, Fernando

AU - Parnell, Grant P.

AU - Mckay, Fiona C.

AU - Gatt, Prudence N.

AU - Shojoei, Maryam

AU - O'Connor, Kate S.

AU - Schibeci, Stephen D.

AU - Brilot, Fabienne

AU - Liddle, Christopher

AU - Batten, Marcel

AU - Stewart, Graeme J.

AU - Booth, David

AU - Baxter, Alan

AU - Kermode, Allan

AU - Carroll, William

AU - Butzkueven, Helmut

AU - Booth, David

AU - Stewart, Graeme

AU - Vucic, Steve

AU - Wiley, James

AU - Field, Judith

AU - Tajouri, Lotti

AU - Griffiths, Lyn

AU - Barnett, Michael

AU - Scott, Rodney

AU - Lechner-Scott, Jeannette

AU - Moscato, Pablo

AU - Broadley, Simon

AU - Slee, Mark

AU - Kilpatrick, Trevor

AU - Taylor, Bruce

AU - Charlesworth, Jac

AU - Brown, Matt

AU - Mason, Deborah

PY - 2014/10/24

Y1 - 2014/10/24

N2 - 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.

AB - 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.

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U2 - 10.1093/hmg/ddt529

DO - 10.1093/hmg/ddt529

M3 - Article

VL - 23

SP - 1425

EP - 1434

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 6

ER -