Genomic Evidence Supports the Recognition of Endometriosis as an Inflammatory Systemic Disease and Reveals Disease-Specific Therapeutic Potentials of Targeting Neutrophil Degranulation.

BACKGROUND

Endometriosis, classically viewed as a localized disease, is increasingly recognized as a systemic disease with multi-organ effects. This disease is highlighted by systemic inflammation in affected organs and by high comorbidity with immune-mediated diseases.

RESULTS

We provide genomic evidence to support the recognition of endometriosis as an inflammatory systemic disease. This was achieved through our genomics-led target prioritization, called ', that leverages the value of multi-layered genomic datasets (including genome-wide associations in disease, regulatory genomics, and protein interactome). Our prioritization recovered existing proof-of-concept therapeutic targeting in endometriosis and outperformed competing prioritization approaches (Open Targets and Naïve prioritization). Target genes at the leading prioritization revealed molecular hallmarks (and possibly the cellular basis as well) that are consistent with systemic disease manifestations. Pathway crosstalk-based attack analysis identified the critical gene . In the context of this gene, we further identified genes that are already targeted by licensed medications in other diseases, such as . Such analysis was supported by current interests targeting the PI3K/AKT/mTOR pathway in endometriosis and by the fact that therapeutic agents targeting are now under active clinical trials in disease. The construction of cross-disease prioritization map enabled the identification of shared and distinct targets between endometriosis and immune-mediated diseases. Shared target genes identified opportunities for repurposing existing immunomodulators, particularly disease-modifying anti-rheumatic drugs (such as , and blockades, and inhibitors). Genes highly prioritized only in endometriosis revealed disease-specific therapeutic potentials of targeting neutrophil degranulation - the exocytosis that can facilitate metastasis-like spread to distant organs causing inflammatory-like microenvironments.

CONCLUSION

Improved target prioritization, along with an atlas of predicted targets and repurposed drugs (available at https://23verse.github.io/end), provides genomic insights into endometriosis, reveals disease-specific therapeutic potentials, and expands the existing theories on the origin of disease.