Druggable Targets for Pelvic Inflammatory Disease: Mendelian Randomization and Experimental Validation

Area of Science:

• Genetics
• Pharmacology
• Gynecology

Background:

• Pelvic inflammatory disease (PID) is a prevalent gynecological condition with significant health impacts.
• Current therapeutic options for PID are limited, necessitating novel treatment strategies.

Purpose of the Study:

• To identify potential therapeutic targets for PID using a drugable genome-wide Mendelian randomization (MR) approach.
• To explore drug repurposing opportunities for PID treatment.

Main Methods:

• Systematic drugable genome-wide MR analysis integrating cis-eQTL and PID GWAS data.
• Colocalization, drug prediction, and molecular docking were employed to identify candidate drugs and targets.
• Validation was performed using a rat model of PID to assess gene expression changes.

Main Results:

• Six key genes were identified through MR, colocalization, and protein interaction analyses.
• Sunitinib and Everolimus were identified as potential drugs targeting Albumin (ALB), Interleukin 6 (IL6), and Cluster of Differentiation 4 (CD4).
• In a PID rat model, ALB and IL6 expression decreased, while CD4 expression increased.

Conclusions:

• Genetic evidence supports ALB, IL6, and CD4 as viable druggable targets for PID.
• Sunitinib and Everolimus demonstrated efficacy in preclinical models, suggesting repurposing potential.
• Differential expression of ALB, IL6, and CD4 was confirmed in vivo in a PID rat model.