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

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.