The CYP 27 B 1 variant associated with increased risk of autoimmune disease is underexpressed in tolerising dendritic cells

Genome-wide association studies have identified a linkage disequilibrium block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyses conversion of 25 Vitamin D3 to 1,25 Vitamin D3. 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 Vitamin D, 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) dendritic cells, and show that for the MS risk allele CYP27B1 is underexpressed in dendritic cells, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolises 1,25 Vitamin D3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced vitamin D 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 Vitamin D effects on DCs. by gest on M ay 2, 2016 ht://hm g.oxfournals.org/ D ow nladed from