Exploration oxidative stress underlying gastroesophageal reflux disease and therapeutic targets identification: a multi-omics Mendelian randomization study

Introduction Gastroesophageal reflux disease (GERD) is a chronic inflammatory gastrointestinal disease, which has no thoroughly effective or safe treatment. Elevated oxidative stress is a common consequence of chronic inflammatory conditions.Methods We employed Summary-data based MR (SMR) analysis to assess the associations between gene molecular characteristics and GERD. Exposure data were the summary-level data on the levels of DNA methylation, gene expression, and protein expression, which obtained from related methylation, expression, and protein quantitative trait loci investigations (mQTL, eQTL, and pQTL). Outcome data, Genome-wide association study (GWAS) summary statistics of GERD, were extracted from the Ong's study (discovery), the D & ouml;nerta & scedil;'s study (replication), and the FinnGen study (replication). Colocalization analysis was performed to determine if the detected signal pairs shared a causative genetic mutation. Oxidative stress related genes and druggable genes were imported to explore oxidative stress mechanism underlying GERD and therapeutic targets of GERD. The Drugbank database was utilized to conduct druggability evaluation.Results After multi-omics SMR analysis and colocalization analysis, we identified seven key genes for GERD, which were SUOX and SERPING1, DUSP13, SULT1A1, LMOD1, UBE2L6, and PSCA. SUOX was screened out to be the mediator, which suggest that GERD is related to oxidative stress. SERPING1, SULT1A1, and PSCA were selected to be the druggable genes.Conclusions These findings offered strong support for the identification of GERD treatment targets in the future as well as for the study of the oxidative stress mechanism underlying GERD. Key Messages What is already known on this topic? - Worries about secondary hypergastrinemia and other side effects linked to long-term PPI usage for gastroesophageal reflux disease (GERD) remain, and ongoing therapy is often necessary. Elevated oxidative stress is a common consequence of many chronic inflammatory conditions. No Mendelian randomization (MR) study has explored the possible causative connection between multi-omics integration data and GERD risk. What this study adds? - The present MR research investigated the possible causal correlations between DNA methylation, gene expression, and protein expression with GERD. We identified a few prospective GERD therapeutic targets and explored the oxidative stress mechanism of GERD. How this study might affect research, practice, or policy? - These results offered strong support for the identification of GERD treatment targets in the future as well as for the study of the oxidative stress mechanism underlying GERD.