Abstract
Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; Padjusted = 2.40x10-11) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (Padjusted = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P<2.2x10-16) and highlighted IFNy and the genetically associated transcription factor BACH2 which showed significantly reduced expression in coeliac samples (log2FC -1.75; Padjusted = 3.6x10-3) as key regulatory genes in CD. Genes regulated by BACH2 were very significantly over-represented among our differentially expressed genes (P<2.2x10-16) indicating that reduced expression of this master regulator of T cell differentiation promotes a pro-inflammatory response and strongly corroborates genetic evidence that BACH2 plays an important role in CD pathogenesis.
Highlights
Coeliac Disease (CD) is defined as a common, chronic inflammatory disease of the small intestine that occurs in genetically predisposed individuals and is triggered by exposure to gluten and similar proteins in related grains[1]
With a known environmental trigger, gluten and the HLA-DQ genes well characterised as genetic risk factors, coeliac disease is one of the best understood of all complex diseases
Recent genome wide association studies (GWAS) and fine mapping studies have identified over 40 CD susceptibility loci
Summary
Coeliac Disease (CD) is defined as a common, chronic inflammatory disease of the small intestine that occurs in genetically predisposed individuals and is triggered by exposure to gluten and similar proteins in related grains[1]. The majority of genetic variants associated with inflammatory diseases, as revealed by GWAS, are located in non-protein coding sequences and are thought to exert their affect by altering the expression of disease associated genes, many of which remain to be definitively identified[8, 9]. By cross referencing with data from gene mapping studies, it may help pinpoint the most likely disease associated genes and genetic variants in the context of specific cells and activation statuses. Such information could potentially be used to refine disease prognosis and risk prediction and may be useful in monitoring disease status[10,11,12]
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