Endoplasmic reticulum stress related genome-wide Mendelian randomization identifies therapeutic genes for ulcerative colitis and Crohn’s disease

Abstract

Background: Endoplasmic reticulum stress (ERS) is an important pathophysiological mechanism in ulcerative colitis (UC) and Crohn’s disease (CD). ERS-related genes may be influenced by genetic factors and intestinal inflammation. However, the role of ERS as a trigger or potential etiological factor for UC and CD is unclear, as the expression of ERS-related genes in UC and CD may be the cause or subsequent changes in intestinal inflammation. Here, we used a three-step summary data-based Mendelian randomization (SMR) approach integrating multi-omics data to identify putative causal effects of ERS-related genes in UC and CD.Methods: Genome-wide association study (GWAS) summary data for UC (6,968 cases and 20,464 controls) and CD (5,956 cases and 14,927 controls) were extracted as outcome, and DNA methylation quantitative trait loci (mQTL, 1,980 participants) data and expression QTL data (eQTL, 31,684 participants) from the blood were obtained as exposure. The ERS-related genes were extracted from the GeneCards database, and then the GWAS summary data were integrated with the mQTL and eQTL data associated with ERS genes by SMR. Sensitivity analysis included two-sample MR analysis, power calculations, Bayesian co-localization analysis, and phenotype scanning were performed to evaluate the robustness of the results.Results: A total of 1,193 ERS-related genes were obtained. The three-step SMR analysis showed that cg24011261 CpG site regulating GPX1 expression was associated with a low risk of UC, whereas GPX1 expression regulated by a combination of cg05055782, cg24011261, and cg05551922 CpG sites was associated with a low risk of CD. Sensitivity analysis further supports these findings.Conclusion: This multi-omics integration study identifies a causal relationship between the role of ERS in UC and CD and suggests potential new therapeutic targets for clinical practice.

Exploring inflammatory bowel disease therapy targets through druggability genes: a Mendelian randomization study

“…Specifically, uses reduced glutathione (GSH) to convert hydrogen peroxide to water and oxidizes GSH to oxidized glutathione (GSSG), which in turn generates GSH again via other reducing enzymes, maintaining the relative balance of GSSH and GSSG (33). Zhou et al demonstrated the connection between endoplasmic reticulum stress-related genes and UC, and CD through a multi-omics approach and discovered that GPX1 expression lowered the risk of UC and CD (34). Oxidative stress leads to the inflammatory response exacerbated by oxidative damage to intracellular DNA, lipids, and proteins, which then triggers an inflammatory response in UC.…”

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

“…SMR integrates and analyzes GWAS summary data with expression quantitative trait loci (eQTL) or DNA methylation quantitative trait loci (mQTL), developed to prioritize causal variation mediated by gene expression or DNA methylation [ 15 ]. Through the application of SMR, a study identified GPX1 as exhibiting a protective effect against UC, indicating its potential as a pharmacological target for these conditions [ 16 ].…”

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

“…Due to the complex role of ER in the normal physiological functions of the cell, dysfunctional behaviour of ER might have serious consequences [2,3,10,20]. ER stress is implicated in a wide range of human diseases [21,22], such as diabetes [23], non-alcoholic fatty acid disease [24], inflammations (including heart diseases [25] and inflammatory bowel disease [26,27]), neurodegeneration (Parkinson's disease [28], Alzheimer's disease [29] and Huntington's disease [30,31]) and also psychiatric diseases [32,33]. Since defects in the proper functioning of the ER are observed in most human diseases and the frequency of ER stress is also increased during aging [34][35][36], it is crucial to study and understand the dynamic behaviour of the regulatory system as comprehensively as possible.…”