Ning Zuodong, Huang Yunying, Lu Haocheng, Zhou Yong, Tu Tao, Ouyang Feifan, Liu Yaozhong, Liu Qiming
Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
Department of Pharmacology, Southern University of Science and Technology, Guangdong, China.
Cardiovasc Drugs Ther. 2024 Dec;38(6):1215-1222. doi: 10.1007/s10557-023-07467-8. Epub 2023 May 22.
Novel, effective, and safe preventive therapy targets for AF are still needed. Circulating proteins with causal genetic evidence are promising candidates. We aimed to systematically screen circulating proteins for AF drug targets and determine their safety and efficacy using genetic methods.
The protein quantitative trait loci (pQTL) of up to 1949 circulating proteins were retrieved from nine large genome-proteome-wide association studies. Two-sample Mendelian Randomization (MR) and colocalization analyses were used to estimate the causal effects of proteins on the risk of AF. Furthermore, phenome-wide MR was conducted to depict side effects and the drug-target databases were searched for drug validation and repurposing.
Systematic MR screen identified 30 proteins as promising AF drug targets. Genetically predicted 12 proteins increased AF risk (TES, CFL2, MTHFD1, RAB1A, DUSP13, SRL, ANXA4, NEO1, FKBP7, SPON1, LPA, MANBA); 18 proteins decreased AF risk (PMVK, UBE2F, SYT11, CHMP3, PFKM, FBP1, TNFSF12, CTSZ, QSOX2, ALAD, EFEMP1, FLRT2, LRIG1, OLA1, SH3BGRL3, IL6R, B3GNT8, FCGR2A). DUSP13 and TNFSF12 possess strong colocalization evidence. For the proteins that were identified, extended phe-MR analysis was conducted to assess their side-effect profiles, while drug-target databases provided information on their approved or investigated indications.
We identified 30 circulating proteins as potential preventive targets for AF.
房颤仍需要新的、有效且安全的预防性治疗靶点。具有因果遗传证据的循环蛋白是很有前景的候选靶点。我们旨在系统筛选循环蛋白作为房颤药物靶点，并使用遗传方法确定其安全性和有效性。
从9项大型全基因组-蛋白质组关联研究中检索了多达1949种循环蛋白的蛋白质定量性状位点（pQTL）。采用两样本孟德尔随机化（MR）和共定位分析来估计蛋白质对房颤风险的因果效应。此外，还进行了全表型组MR以描述副作用，并搜索药物靶点数据库以进行药物验证和重新利用。
系统的MR筛选确定了30种蛋白作为有前景的房颤药物靶点。基因预测有12种蛋白增加房颤风险（TES、CFL2、MTHFD1、RAB1A、DUSP13、SRL、ANXA4、NEO1、FKBP7、SPON1、LPA、MANBA）；18种蛋白降低房颤风险（PMVK、UBE2F、SYT11、CHMP3、PFKM、FBP1、TNFSF12、CTSZ、QSOX2、ALAD、EFEMP1、FLRT2、LRIG1、OLA1、SH3BGRL3、IL6R、B3GNT8、FCGR2A）。DUSP13和TNFSF12具有很强的共定位证据。对于已鉴定的蛋白，进行了扩展的全表型组MR分析以评估其副作用谱，同时药物靶点数据库提供了有关其已批准或正在研究的适应症的信息。
我们确定了30种循环蛋白作为房颤的潜在预防靶点。
