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

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

doi:10.1007/s10557-023-07467-8

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

Cardiovasc Drugs Ther. 2023 May 22. doi: 10.1007/s10557-023-07467-8. Online ahead of print.

Authors

Zuodong Ning^#¹, Yunying Huang^#¹, Haocheng Lu², Yong Zhou¹, Tao Tu¹, Feifan Ouyang³, Yaozhong Liu^{4

5}, Qiming Liu⁶

Affiliations

¹ Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
² Department of Pharmacology, Southern University of Science and Technology, Guangdong, China.
³ Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.
⁴ Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China. yaozhongliu@csu.edu.cn.
⁵ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor MI, MI, USA. yaozhongliu@csu.edu.cn.
⁶ Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China. qimingliu@csu.edu.cn.

^# Contributed equally.

PMID: 37212950
DOI: 10.1007/s10557-023-07467-8

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.

Keywords: Atrial fibrillation; Circulating proteins; Drug targets; Mendelian randomization analysis.

Abstract

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