通过多血统孟德尔随机化探索胆结石潜在的血浆药物靶点。
Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization.
作者信息
Liu Xiaoduo, Shi Lubo, Zhang Shutian, Zhou Anni
机构信息
Department of Neurology and Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders.
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing Digestive Disease Center, National Clinical Research Center for Digestive Diseases, Beijing, People's Republic of China.
出版信息
Int J Surg. 2025 Jan 1;111(1):302-310. doi: 10.1097/JS9.0000000000001925.
BACKGROUND
Cholelithiasis poses significant health and economic burdens, necessitating novel pharmacological targets to enhance treatment efficacy.
METHOD
Based on genome-wide association analysis studies, the authors performed a two-sample Mendelian randomization (MR) analysis based on plasma proteomics to explore potential drug targets in European (n Case =40 191 and n Control =361 641) and Asian (n Case =9305 and n Control =168 253) populations. The authors confirmed the directionality and robust correlation of the drug targets with the results through reverse MR analysis, Steiger filtering, Bayesian colocalization, phenotype scanning, and replication in multiple databases. Further exploration of the safety and possible mechanisms of action of phenome-wide MR analysis and protein-protein interactions (PPIs) as individual drug targets was performed.
RESULTS
Our proteomics-based MR analyses suggested that FUT3 (OR=0.87; 95% CI: 0.84-0.89; P =4.70×10 -32 ), NOE1 (OR=0.58; 95% CI: 0.52-0.66; P =4.21×10 -23 ), UGT1A6 (OR=0.68; 95% CI: 0.64-0.73; P =9.58×10 -30 ), and FKBP52 (OR=1.75; 95% CI: 1.37-2.24; P =8.61×10 -6 ) were potential drug targets in Europeans, whereas KLB (OR=1.11; 95% CI: 1.07-1.16; P =7.59×10 -7 ) and FGFR4 (OR=0.94; 95% CI: 0.91-0.96; P =4.07×10 -6 ) were valid targets in East Asians. There was no reverse causality for these drug targets. Evidence from Bayesian colocalization analyses supported that exposure and outcome shared consistent genetic variables. Phenome-wide MR analysis suggested the potential deleterious effects of NOE1 and FGFR4. PPI analysis confirmed the pathways associated with the potential targets involved in bile acid metabolism.
CONCLUSIONS
Genetically predicted levels of the plasma proteins FUT3, NOE1, UGT1A6, and FKBP52 have the potential as prospective targets in Europeans. Moreover, the plasma levels of KLB and FGFR4 may serve as potential targets for the treatment of cholelithiasis in East Asians.
背景
胆结石带来了重大的健康和经济负担，因此需要新的药理学靶点来提高治疗效果。
方法
基于全基因组关联分析研究，作者基于血浆蛋白质组学进行了两样本孟德尔随机化（MR）分析，以探索欧洲人群（病例组n = 40191，对照组n = 361641）和亚洲人群（病例组n = 9305，对照组n = 168253）中的潜在药物靶点。作者通过反向MR分析、Steiger过滤、贝叶斯共定位、表型扫描以及在多个数据库中的重复验证，确认了药物靶点与结果的方向性和强相关性。进一步探索了全表型组MR分析和蛋白质-蛋白质相互作用（PPI）作为个体药物靶点的安全性和可能的作用机制。
结果
我们基于蛋白质组学的MR分析表明，FUT3（比值比[OR]=0.87；95%置信区间[CI]：0.84 - 0.89；P = 4.70×10⁻³²）、NOE1（OR = 0.58；95% CI：0.52 - 0.66；P = 4.21×10⁻²³）、UGT1A6（OR = 0.68；95% CI：0.64 - 0.73；P = 9.58×10⁻³⁰）和FKBP52（OR = 1.75；95% CI：1.37 - 2.24；P = 8.61×10⁻⁶）是欧洲人的潜在药物靶点，而KLB（OR = 1.11；95% CI：1.07 - 1.16；P = 7.59×10⁻⁷）和FGFR4（OR = 0.94；95% CI：0.91 - 0.96；P = 4.07×10⁻⁶）是东亚人的有效靶点。这些药物靶点不存在反向因果关系。贝叶斯共定位分析的证据支持暴露和结果共享一致的遗传变量。全表型组MR分析表明NOEⅠ和FGFR4具有潜在的有害作用。PPI分析证实了与胆汁酸代谢相关潜在靶点的通路。
结论
血浆蛋白FUT3、NOE1、UGT1A6和FKBP52的遗传预测水平有潜力作为欧洲人的前瞻性靶点。此外，KLB和FGFR4的血浆水平可能作为东亚人胆结石治疗的潜在靶点。
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