The effects of plasma protein levels on the risk of endometriosis: A Mendelian randomization study

Endometriosis is a prevalent gynecologic disorder that significantly impacts women's health. However, its underlying pathogenesis remains unknown. This study aimed to ascertain causal associations between plasma protein levels and endometriosis using a Mendelian randomization (MR) design. Plasma protein genome-wide association studies (GWAS) data originating from the UK Biobank Pharma Proteomics Project (UKB-PPP) were utilized as exposure variables. Endometriosis GWAS data from the FinnGen study and UKB study served as outcome variables at the discovery and replication stages, respectively. Summary-data-based MR (SMR) and instrument-dependent heterogeneity (HEIDI) tests were conducted to further validate the relationships between proteins and the risk of endometriosis. Genetic variations between the identified plasma proteins and endometriosis were investigated by colocalization analyses. The proteome‑wide MR and SMR results revealed that genetically predicted plasma levels of proteins (RSPO3, WASHC3, FSHB, and VEGFB) were positively associated with the risk of endometriosis. Among them, only FSHB and RSPO3 passed the HEIDI tests, and colocalization analyses further supported their causal relationship with endometriosis. Based on large-scale population GWAS data, our research demonstrated causal correlations of FSHB and RSPO3 with the risk of endometriosis. These findings suggest that plasma proteins are involved in the development of endometriosis and may serve as potential biomarkers and therapeutic targets for this complicated disease in the future.