Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization

孟德尔随机化 医学 药品 全基因组关联研究 药物基因组学 CYP2B6型 计算生物学 生物信息学 内科学 药理学 遗传学 单核苷酸多态性 细胞色素P450 CYP3A4型 基因 遗传变异 生物 基因型 新陈代谢
作者
Xiaoduo Liu,Lubo Shi,Shutian Zhang,Anni Zhou
出处
期刊:International Journal of Surgery [Wolters Kluwer]
标识
DOI:10.1097/js9.0000000000001925
摘要

Background: Cholelithiasis poses significant health and economic burdens, necessitating novel pharmacological targets to enhance treatment efficacy. Method: Based on genome-wide association analysis (GWAS) studies, we performed 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 =9,305 and n Control =168,253) populations. We 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 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.
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