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Celiac disease (CeD) is a complex immune-mediated disease. Genetic studies have implicated 43 predisposing loci that collectively explain some 50% of the genetic variance in CeD. More than ∼90% of CeD-associated single nucleotide polymorphisms (SNPs) localize to the non-coding genome, which we need to better understand to translate genetic knowledge into clinical practice. New genomic technologies and resources are permitting a systematic analysis of the functional elements in the non-coding part of the genome. Here we explain how investigating the regulatory and epigenomic landscape will help to pinpoint the cell types involved in CeD, and the driver genes and gene regulatory networks that are affected by CeD-associated SNPs. [ABSTRACT FROM AUTHOR]

Celiac disease is characterized by a chronic inflammatory reaction in the intestine and is triggered by gluten, a constituent derived from grains which is present in the common daily diet in the Western world. Despite decades of research, the mechanisms behind celiac disease etiology are still not fully understood, although it is clear that both genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by genome-wide association studies. These have uncovered a wealth of information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in celiac disease, focusing on the 'non-HLA' genes. We also present novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms. [ABSTRACT FROM AUTHOR]

The respective effects of tissue alarmins interleukin (IL)-15 and interferon beta (IFNβ), and IL-21 produced by T cells on the reprogramming of cytotoxic T lymphocytes (CTLs) that cause tissue destruction in celiac disease is poorly understood. Transcriptomic and epigenetic profiling of primary intestinal CTLs showed massive and distinct temporal transcriptional changes in response to tissue alarmins, while the impact of IL-21 was limited. Only anti-viral pathways were induced in response to all the three stimuli, albeit with differences in dynamics and strength. Moreover, changes in gene expression were primarily independent of changes in H3K27ac, suggesting that other regulatory mechanisms drive the robust transcriptional response. Finally, we found that IL-15/IFNβ/IL-21 transcriptional signatures could be linked to transcriptional alterations in risk loci for complex immune diseases. Together these results provide new insights into molecular mechanisms that fuel the activation of CTLs under conditions that emulate the inflammatory environment in patients with autoimmune diseases. • We report the epigenetic and transcriptomic response of IE-CTLs to tissue-derived alarmins and adaptive cytokine. • IL-15 and IFNβ induce massive and distinct transcriptional changes in IE-CTLs, while the impact of IL-21 was limited. • Genes associated with immune-mediated intestinal diseases are enriched in genes responding to IL-15, IFNβ and IL-21 in IE-CTLs. [ABSTRACT FROM AUTHOR]