Table2_Identifying celiac disease-related chemicals by transcriptome-wide association study and chemical-gene interaction analyses.XLSX

Celiac disease (CeD) is one of the most common intestinal inflammatory diseases, and its incidence and prevalence have increased over time. CeD affects multiple organs and systems in the body, and environmental factors play a key role in its complex pathogenesis. Although gluten exposure is known to be the causative agent, many unknown environmental factors can trigger or exacerbate CeD. In this study, we investigated the influence of genetic and environmental factors on CeD. Data from a CeD genome-wide association study that included 12,041 CeD cases and 12,228 controls were used to conduct a transcriptome-wide association study (TWAS) using FUSION software. Gene expression reference data were obtained for the small intestine, whole blood, peripheral blood, and lymphocytes. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significant genes identified by the TWAS and conducted a protein–protein interaction network analysis based on the STRING database to detect the function of TWAS-identified genes for CeD. We also performed a chemical-related gene set enrichment analysis (CGSEA) using the TWAS-identified genes to test the relationships between chemicals and CeD. The TWAS identified 8,692 genes, including 101 significant genes (padjusted < 0.05). The CGSEA identified 2,559 chemicals, including 178 chemicals that were significantly correlated with CeD. This study performed a TWAS (for genetic factors) and CGSEA (for environmental factors) and identified several CeD-associated genes and chemicals. The findings expand our understanding of the genetic and environmental factors related to immune-mediated diseases.

乳糜泻（Celiac disease, CeD）是最常见的肠道炎性疾病之一，其发病率与患病率随时间呈上升趋势。该疾病可累及机体多个器官与系统，环境因素在其复杂的发病机制中发挥关键作用。尽管已知麸质暴露是其致病诱因，但仍有诸多不明环境因素可诱发或加重乳糜泻。本研究旨在探讨遗传与环境因素对乳糜泻的影响。本研究纳入包含12041例乳糜泻患者与12228例对照的全基因组关联研究（genome-wide association study）数据，借助FUSION软件开展转录组全关联研究（transcriptome-wide association study, TWAS），并获取了小肠、全血、外周血以及淋巴细胞的基因表达参考数据集。本研究针对转录组全关联研究筛选出的显著基因，开展基因本体论（Gene Ontology, GO）与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）富集分析，并基于STRING数据库（STRING database）构建蛋白质相互作用网络，以解析乳糜泻相关转录组全关联研究筛选基因的功能。此外，本研究利用转录组全关联研究筛选出的基因开展化学物相关基因集富集分析（chemical-related gene set enrichment analysis, CGSEA），以探究化学物与乳糜泻之间的关联。转录组全关联研究共筛选出8692个基因，其中101个为显著基因（校正后P值<0.05）。化学物相关基因集富集分析共筛选出2559种化学物，其中178种与乳糜泻存在显著关联。本研究通过转录组全关联研究（针对遗传因素）与化学物相关基因集富集分析（针对环境因素），筛选出多个与乳糜泻相关的基因与化学物。本研究结果加深了我们对免疫介导性疾病相关遗传与环境因素的认知。