Zhou Jie, Xu Yixin, Wang Haitao, Chen Chao, Wang Kun
Department of General Surgery, The Wujin Hospital Affiliated with Jiangsu University Changzhou 213003, Jiangsu, China.
Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University Changzhou 213003, Jiangsu, China.
Am J Transl Res. 2025 Feb 15;17(2):1076-1086. doi: 10.62347/BTYN8678. eCollection 2025.
This study seeks to identify new drug targets for Primary Sclerosing Cholangitis (PSC), a condition currently lacking effective treatment, to improve survival without transplantation.
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.
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, = 6.85E-07, FDR = 0.002).
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.
本研究旨在确定原发性硬化性胆管炎（PSC）的新药物靶点，目前该疾病缺乏有效治疗方法，本研究旨在提高患者在不进行移植情况下的生存率。
我们分别从eQTLGen联盟和芬兰基因联盟获得了2888个可成药基因和PSC的汇总统计数据。通过使用逆方差加权（IVW）方法的两样本孟德尔随机化，我们确定了错误发现率（FDR）<0.05的与PSC相关的基因。进一步的验证来自共定位和基于汇总数据的孟德尔随机化（SMR）分析，证实了我们结果的可靠性。
在FDR<0.05的情况下，五个可成药基因与PSC存在因果关系。随后的共定位和SMR分析进一步证实，血浆中较高水平的CDC42与PSC风险增加相关（IVW方法：优势比1.319，95%置信区间1.182 - 1.471， = 6.85E - 07，FDR = 0.002）。
我们的研究率先确定CDC42为减缓PSC进展的靶点。我们的研究不仅揭示了一个可能的药物靶点，还为PSC治疗药物的开发提供了方向。
