Novel Drug Targets for Atrial Fibrillation Identified Through Mendelian Randomization Analysis of the Blood Proteome.

IF 3.1 3区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Drugs and Therapy Pub Date : 2024-12-01 Epub Date: 2023-05-22 DOI:10.1007/s10557-023-07467-8

Zuodong Ning, Yunying Huang, Haocheng Lu, Yong Zhou, Tao Tu, Feifan Ouyang, Yaozhong Liu, Qiming Liu

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Abstract

Purpose: 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.

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.

Results: 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.

Conclusion: We identified 30 circulating proteins as potential preventive targets for AF.

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通过血液蛋白质组的孟德尔随机化分析确定心房颤动的新药物靶点。

目的：新的、有效的、安全的房颤预防治疗靶点仍然需要。具有因果遗传证据的循环蛋白是有希望的候选者。我们的目的是系统地筛选循环蛋白作为AF药物靶点，并利用遗传方法确定其安全性和有效性。方法：从9个大型基因组-蛋白质组关联研究中检索到多达1949个循环蛋白的蛋白质数量性状位点（pQTL）。使用双样本孟德尔随机化（MR）和共定位分析来估计蛋白质对房颤风险的因果关系。此外，进行全现象MR来描述副作用，并搜索药物靶点数据库以进行药物验证和重新利用。结果：系统MR筛选鉴定出30个有希望的AF药物靶点蛋白。基因预测12种蛋白增加AF风险（TES、CFL2、MTHFD1、RAB1A、DUSP13、SRL、ANXA4、NEO1、FKBP7、SPON1、LPA、MANBA）；18种蛋白（PMVK、UBE2F、SYT11、CHMP3、PFKM、FBP1、TNFSF12、CTSZ、QSOX2、ALAD、EFEMP1、FLRT2、LRIG1、OLA1、SH3BGRL3、IL6R、B3GNT8、FCGR2A）降低了AF风险。DUSP13和TNFSF12具有很强的共定位证据。对于已鉴定的蛋白质，进行了扩展的phe-MR分析以评估其副作用概况，同时药物靶标数据库提供了其批准或研究适应症的信息。结论：我们确定了30种循环蛋白作为AF的潜在预防靶点。

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来源期刊

Cardiovascular Drugs and Therapy 医学-心血管系统

CiteScore

8.30

自引率

0.00%

发文量

110

审稿时长

4.5 months

期刊介绍： Designed to objectively cover the process of bench to bedside development of cardiovascular drug, device and cell therapy, and to bring you the information you need most in a timely and useful format, Cardiovascular Drugs and Therapy takes a fresh and energetic look at advances in this dynamic field. Homing in on the most exciting work being done on new therapeutic agents, Cardiovascular Drugs and Therapy focusses on developments in atherosclerosis, hyperlipidemia, diabetes, ischemic syndromes and arrhythmias. The Journal is an authoritative source of current and relevant information that is indispensable for basic and clinical investigators aiming for novel, breakthrough research as well as for cardiologists seeking to best serve their patients. Providing you with a single, concise reference tool acknowledged to be among the finest in the world, Cardiovascular Drugs and Therapy is listed in Web of Science and PubMed/Medline among other abstracting and indexing services. The regular articles and frequent special topical issues equip you with an up-to-date source defined by the need for accurate information on an ever-evolving field. Cardiovascular Drugs and Therapy is a careful and accurate guide through the maze of new products and therapies which furnishes you with the details on cardiovascular pharmacology that you will refer to time and time again.