Discovery of potential new drug targets for cystitis and chronic cystitis: A drug target Mendelian randomization study.

BACKGROUND

Acute cystitis is a common bacterial infection, and its progression to chronic forms poses significant challenges due to limitations of antibiotic therapy. We aimed to identify novel drug targets for cystitis using a Mendelian randomization approach.

METHODS

We integrated plasma protein data (from DECODE and UKB-PPP) and eQTL data (from eqtlGEN) as exposures, with cystitis (FinnGEN) and chronic cystitis (LeeLab) data as outcomes. Analyses included MR, SMR, Bayesian colocalization, and HEIDI tests. Promising targets underwent druggability assessment, PheWAS, and PPI analysis.

RESULTS

We identified eight potential targets for cystitis and one specific to chronic cystitis. Positive regulators included BTN3A2, H2BC5, HLA-DQA1, HLA-DQB1, and MARK3; negative regulators were TNXB, BTN2A1, and HLA-DQB2. MYCBPAP was a negative regulator specific to chronic cystitis. After validation, MARK3 and HLA-DQA1 were classified as Tier 2 (druggable), MYCBPAP as Tier 1, and others as Tier 3. PheWAS and PPI analyses indicated no major side effects or interactions for MARK3 and HLA-DQA1.

CONCLUSION

MARK3 and HLA-DQA1 are promising drug targets for cystitis. Inhibition of these proteins may offer therapeutic benefits. Further experimental validation is required. MYCBPAP represents a specific potential target for chronic cystitis, warranting future investigation.

LEVEL OF EVIDENCE: Level II, Mendelian randomization study.