Zou Menglong, Liang Qiaoli, Zhang Wei, Zhu Ying, Xu Yin
The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
Zhuhai Second Hospital of Chinese Medicine, Zhuhai, Guangdong, China.
Front Genet. 2023 Oct 4;14:1270085. doi: 10.3389/fgene.2023.1270085. eCollection 2023.
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. 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. A total of 1,193 ERS-related genes were obtained. The three-step SMR analysis showed that cg24011261 CpG site regulating expression was associated with a low risk of UC, whereas 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. 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.
内质网应激（ERS）是溃疡性结肠炎（UC）和克罗恩病（CD）的一种重要病理生理机制。与ERS相关的基因可能受遗传因素和肠道炎症的影响。然而，ERS作为UC和CD的触发因素或潜在病因的作用尚不清楚，因为UC和CD中与ERS相关基因的表达可能是肠道炎症的原因或后续变化。在此，我们采用一种整合多组学数据的基于三步汇总数据的孟德尔随机化（SMR）方法，以确定与ERS相关基因在UC和CD中的假定因果效应。提取UC（6968例病例和20464例对照）和CD（5956例病例和14927例对照）的全基因组关联研究（GWAS）汇总数据作为结果，并获取来自血液的DNA甲基化定量性状位点（mQTL，1980名参与者）数据和表达定量性状位点（eQTL，31684名参与者）数据作为暴露因素。从基因卡片数据库中提取与ERS相关的基因，然后通过SMR将GWAS汇总数据与与ERS基因相关的mQTL和eQTL数据整合。敏感性分析包括两样本孟德尔随机化分析、效能计算、贝叶斯共定位分析，并进行表型扫描以评估结果的稳健性。共获得1193个与ERS相关的基因。三步SMR分析表明，调控表达的cg24011261 CpG位点与UC低风险相关，而由cg05055782、cg24011261和cg05551922 CpG位点组合调控的表达与CD低风险相关。敏感性分析进一步支持了这些发现。这项多组学整合研究确定了ERS在UC和CD中的作用之间的因果关系，并为临床实践提出了潜在的新治疗靶点。
