Identifying therapeutic targets for kidney stone disease through proteome-wide Mendelian randomization and...

Area of Science:

• Genetics
• Pharmacology
• Nephrology

Background:

• Kidney stone disease (KSD) presents increasing global prevalence and recurrence.
• Mendelian randomization (MR) is a valuable tool for drug repurposing and identifying therapeutic targets.

Purpose of the Study:

• To identify protein targets for KSD treatment using a proteome-wide MR approach.
• To assess potential adverse drug reactions associated with these protein targets.
• To discover novel therapeutic strategies for KSD prevention and management.

Main Methods:

• A proteome-wide Mendelian randomization study was conducted using UK Biobank proteomics data (2940 proteins).
• Genome-wide association study data for KSD from FinnGen (10,556 cases, 400,681 controls) were analyzed.
• Colocalization analysis and Phenome-wide association studies (PheWAS) were employed to identify shared causal variants and explore adverse drug reactions.

Main Results:

• MR analysis revealed positive correlations between KSD risk and proteins ITIH4, F12, and FKBPL.
• Negative correlations with KSD risk were observed for DAG1, ITIH1, LTB, and CACYBP (Pfdr < 0.05).
• CACYBP emerged as the most promising druggable protein target for preventing KSD recurrence, supported by colocalization and PheWAS.

Conclusions:

• This study identified key genetic protein biomarkers associated with KSD risk.
• CACYBP is highlighted as a potential therapeutic target for KSD prevention and treatment.
• The findings offer novel insights into drug repurposing and side effect prediction for KSD management.