CDC42: unlocking a novel therapeutic target for primary sclerosing cholangitis through Mendelian randomization.

Abstract

Objectives: This study seeks to identify new drug targets for Primary Sclerosing Cholangitis (PSC), a condition currently lacking effective treatment, to improve survival without transplantation.

Methods: We obtained summary statistics for 2,888 druggable genes and PSC from the eQTLGen Consortium and the FinnGen consortium, respectively. Through two-sample Mendelian randomization using the Inverse Variance Weighted (IVW) method, we identified genes associated with PSC at a False Discovery Rate (FDR) < 0.05. Further validation came from colocalization and Summary-data-based Mendelian Randomization (SMR) analyses, confirming the reliability of our results.

Results: Five druggable genes were causally associated with PSC at FDR < 0.05. Subsequent colocalization and SMR analyses further confirmed that higher levels of CDC42 in plasma were associated with an increased risk of PSC (IVW method: Odds Ratio 1.319, 95% Confidence Interval 1.182-1.471, P = 6.85E-07, FDR = 0.002).

Conclusions: Our research pioneered the identification of CDC42 as a target for slowing PSC progression. Our research not only uncovers a possible drug target but also provides direction for the development of therapeutics for PSC.