Identifying Novel Biomarkers and Therapeutic Targets for Endometriosis: Integrative Analysis of the Plasma Proteome and Genome

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BACKGROUND: There is currently no consensus on the etiology, pathogenesis, or treatment of endometriosis (EM). The discovery of disease-associated plasma proteins with causal genetic evidence provides an opportunity to identify new EM biomarkers and therapeutic targets. METHODS: Protein quantitative trait loci (pQTLs) were derived from plasma proteomic associations in the UK Biobank Pharma Proteomics Project (UKB-PPP). Genetic associations with EM were obtained from the FinnGen cohort. The associations between proteins and the risk of EM were estimated by cis-Mendelian randomization (cis-MR) and validated using the GWAS catalog dataset of EM. Colocalization, protein-protein interaction (PPI) analysis, functional enrichment analysis, transcriptome differential expression gene (DEG) analysis and druggability evaluation were further performed to explore potential biomarkers and therapeutic targets for EM. RESULTS: Overall, genetically predicted levels of 23 plasma proteins were associated with EM risk, with five proteins validated via replication analysis (ALPI, KHK, HSPG2, STXBP1, and POLR2F). Lower levels of genetically predicted ALPI (odds ratio [OR]: 0.89, 95% confidence interval [CI] 0.83-0.95), HSPG2 (OR: 0.81, 95% CI 0.75-0.88), POLR2F (OR: 0.51, 95% CI 0.36-0.73), and STXBP1 (OR: 0.75, 95% CI 0.64-0.86) were associated with an increased risk of EM. Elevated levels of KHK (OR: 1.09, 95% CI 1.05-1.13) were associated with an increased risk of EM. We also identified ALPI, KHK, HSPG2, STXBP1, and POLR2F as potential drug targets and biomarkers for EM. CONCLUSION: A series of comprehensive analyses emphasized the potential role of ALPI, KHK, HSPG2, STXBP1, and POLR2F in EM and suggested that these genes could be developed into exact biomarkers and therapeutic targets for this condition in future research.

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