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

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Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

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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Data Availability

Cis-instruments were queried in the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/). The open-access drug target database (Drugbank: https://go.drugbank.com/; Therapeutic Target Database: http://db.idrblab.net/ttd/; Clinical trial: https://clinicaltrials.gov/) was searched to identify records on past or present clinical drug development programs.

Code availability

Contact the corresponding author for reasonable use.

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Acknowledgements

This study used summary statistics from large genetic consortia. The authors gratefully acknowledge their contributions to making their datasets publicly available, without which this study would not be possible.

Funding

This work was supported by grants from the Hunan Province Innovative Project (no. 2020SK1013), the National Natural Science Foundation of China (no. 82070356) and the Hunan Provincial Natural Science Foundation of China (no. 2021JJ30033, no. 2021JJ40870).

Author information

Author notes

  1. Zuodong Ning and Yunying Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China

    Zuodong Ning, Yunying Huang, Yong Zhou, Tao Tu, Yaozhong Liu & Qiming Liu

  2. Department of Pharmacology, Southern University of Science and Technology, Guangdong, China

    Haocheng Lu

  3. Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany

    Feifan Ouyang

  4. Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor MI, MI, USA

    Yaozhong Liu

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  1. Zuodong Ning
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and software analysis were performed by Zuodong Ning, Yong Zhou and Haochen Lu. The first draft of the manuscript was written by Yunying Huang and all authors commented on previous versions of the manuscript. The validation of data was performed by Feifan Ouyang and the whole project was supervised by Yaozhong Liu. Funding was acquired by Tao Tu and Qiming Liu. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yaozhong Liu or Qiming Liu.

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What’s New?

1. Our study systematically screens circulating proteins for AF drug targets and determines their safety and efficacy using genetic methods.

2. We identified 30 proteins as potential preventive drug targets for AF, by using the two-sample MR analysis to evaluate causal roles of 1949 circulating proteins on AF, with a sample size exceeding 1 million. Our finding expands the knowledge regarding the AF prevention targets currently known.

Supplementary information

ESM 1:

Supplementary Table 1. Databases involved in reserch. Supplementary Table 2. The cis-pQTL instuments for 1,949 circulating proteins. Supplementary Table 3. The causal effect of 1,949 circulating proteins on AF risk. Supplementary Table 4. The causal effect of 30 proteins as preventive drug targets on AF. Supplementary Table 5. The colocalization analysis results of the 30 proteins. Supplementary Table 6. The phe-MR analysis results of the 30 proteins. Supplementary Table 7. Potential repurposing opportunities of approved drugs and novel drugs under development.

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Ning, Z., Huang, Y., Lu, H. et al. Novel Drug Targets for Atrial Fibrillation Identified Through Mendelian Randomization Analysis of the Blood Proteome. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07467-8

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  • DOI: https://doi.org/10.1007/s10557-023-07467-8

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