Objective  To explore the causal relationship between epilepsy (EP) and type 1 diabetes mellitus (T1DM) based on Mendelian randomization (MR) method, and to apply bioinformatics analysis to screen the key genes of EP and T1DM.

Methods  Relevant data of EP and T1DM was obtained from the IEU Open GWAS Project database. Single nucleotide polymorphisms (SNPs) significantly associated with exposure factors were selected as instrumental variables. The inverse variance weighted (IVW) method was the main method of MR analysis, and odds ratio (OR) was adopted to analyze the causal relationship between EP and T1DM. The gene chip dataset of EP and T1DM were downloaded through the Gene Expression Omnibus (GEO) database, and common differentially genes were taken for enrichment analysis. The Cytohubba toolkit of Cytoscape software was used to obtain the genes with the top 10 Degree values and screen the key genes to explore the common mechanism of EP and T1DM.

Results  The results of MR analysis showed that generalized epilepsy (GE) was a risk factor for T1DM (OR=1.173, 95%CI: 1.007-1.367, P=0.040). The results of bioinformatic analysis showed that there were 12 common differential genes between EP and T1DM, namely CD69, CXCL1, DACH1, ELANE, FOLR3, HBB, HIST2H2BE, HP, PMP22, PTGDS, SKAP1 and TAGAP. The results of Gene Ontology (GO) analysis showed that the biological process (BP) of common differential gene was mainly enriched in antimicrobial humoral immune response mediated by antimicrobial peptide, acute inflammatory response, myeloid leukocyte mediated immunity, etc.; cellular component (CC) was mainly enriched in specific granule lumen, tertiary granule lumen, specific granule, secretory granule lumen, cytoplasmic vesicle lumen, vesicle lumen, tertiary granule, etc.; molecular function (MF) was mainly enriched in organic acid binding, serine-type endopeptidase activity, serine-type peptidase activity, serine hydrolase activity, etc. The results of Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis showed that the common differential genes were enriched in antifolate resistance, folate transport and metabolism, African trypanosomiasis, malaria, legionellosis, arachidonic acid metabolism, epithelial cell signaling in Helicobacter pylori infection. The key genes HBB, PMP22, HP, FOLR3, CD69, DACH1, ELANE, and PTGDS may be biomarkers or therapeutic targets for EP and T1DM.

Conclusion  GE was one of the risk factors for T1DM and HBB, PMP22, HP, FOLR3, CD69, DACH1, ELANE, and PTGDS may be the key argets for the treatment of EP and T1DM.

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