Scripties UMCG - Rijksuniversiteit Groningen
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Exploring the role of candidate causal genes in CeD pathology Insights from disease phenotypes, co-expression and pathways enrichment

(2018) Hudepohl, A.

Celiac disease (CeD) is a chronic immune-mediated enteropathy induced by ingestion of gluten. Apart from the well-known association to human leukocyte antigen (HLA), genetic studies have identified multiple genetic risk variants involved in CeD susceptibility; however, the translation of those variants to causal single nucleotide polymorphisms (SNPs) and genes remains a major challenge. Expression quantitative trait locus (eQTL) mapping studies help to prioritize potentially causal genes. Still, how these candidate genes relate to CeD disease biology is unclear. The aim of this study is to gain insight into the role of potentially causal genes in the pathogenesis of CeD.
For this purpose, the most recent prioritized list of cis-eQTLgenes associated with CeD was compared to genes involved in monogenic immune disorders (MIDs) and to genes associated with phenotypic abnormalities described in the Human Phenotype Ontology(HPO). In both comparisons, an enrichment analysis was performed. Additionally, a co-expression analysis followed by a Reactome pathway enrichment analysis were carried out.
MIDs highlighted a possible role of multiple candidate cis-eQTLgenes in the different parts of the immune system, including T and B cell functions, eosinophil and neutrophil function. HPO enrichment analysis showed even more candidate genes are involved in autoimmunity and the systemic pattern of inflammation, described in CeD. Coexpression and pathway enrichment analysis showed one clear cluster of coexpressed candidate genes involved in T cell signaling pathways.
In conclusion, these methods give biological insight to some of the prioritized cis-eQTL genes and point out interesting candidate genes to further investigate in future functional research to determine their role in CeD pathology.

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