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CDC42: unlocking a novel therapeutic target for primary sclerosing cholangitis through Mendelian randomization
Jie Zhou1,2, Yixin Xu1,2, Haitao Wang3
1Department of General Surgery, The Wujin Hospital Affiliated with Jiangsu University Changzhou 213003, Jiangsu, China.
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.
Insights
This study identified CDC42 as a potential drug target for Primary Sclerosing Cholangitis (PSC). Targeting CDC42 may help slow PSC progression and improve patient outcomes without transplantation.
Area of Science:
- Genetics
- Pharmacology
- Hepatology
Background:
- Primary Sclerosing Cholangitis (PSC) is a chronic liver disease with limited treatment options, often necessitating liver transplantation.
- Identifying novel therapeutic targets is crucial for improving patient survival and quality of life.
Purpose of the Study:
- To discover novel druggable gene targets for Primary Sclerosing Cholangitis (PSC).
- To identify potential therapeutic strategies to slow PSC progression and improve outcomes.
Main Methods:
- Utilized two-sample Mendelian randomization (MR) with summary statistics from eQTLGen and FinnGen consortia.
- Analyzed 2,888 druggable genes for causal association with PSC using Inverse Variance Weighted (IVW) method.
- Validated findings through colocalization and Summary-data-based Mendelian Randomization (SMR) analyses.
Main Results:
- Identified five druggable genes causally associated with PSC at a False Discovery Rate (FDR) < 0.05.
- Confirmed a causal link between elevated plasma CDC42 levels and increased PSC risk (OR 1.319, P = 6.85E-07).
- Colocalization and SMR analyses supported the reliability of the identified gene-PSC association.
Conclusions:
- Pioneered the identification of CDC42 as a novel therapeutic target for PSC.
- Provides a potential avenue for developing new treatments to slow PSC progression.
- Offers direction for future drug development in PSC therapeutics.
