Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation

• Published in: PloS one 2015-10, Vol.10 (10), p.e0140049-e0140049
• Main Authors: Quinn, Emma M, Coleman, Ciara, Molloy, Ben, Dominguez Castro, Patricia, Cormican, Paul, Trimble, Valerie, Mahmud, Nasir, McManus, Ross
• Format: Article
• Language: English
• Subjects: Adult; Aged; Autoimmune diseases; Basic-Leucine Zipper Transcription Factors - genetics; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Celiac disease; Celiac Disease - genetics; Celiac Disease - pathology; Cell differentiation; Clinical medicine; Cytokines; Differentiation (biology); Disease; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene regulation; Gene Regulatory Networks; Gene sequencing; Genes; Genetic diversity; Genetic variance; Genetics; Genome-Wide Association Study; Genomes; Gluten; Health risk assessment; Hospitals; Humans; Immunology; Inflammation; Inflammatory response; Interferon-gamma - genetics; Kinases; Lymphocytes; Lymphocytes T; Male; Medicine; Middle Aged; Modules; Network analysis; Pathogenesis; Ribonucleic acid; RNA; Sequence Analysis, RNA; Studies; T cell receptors; Transcriptome; Young Adult; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140049

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; P(adjusted) = 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 (P(adjusted) = 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