Journal article
Plasma proteomics to identify drug targets for ischemic heart disease
- Abstract:
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Background
Integrated analyses of plasma proteomic and genetic markers in prospective studies can clarify the causal relevance of proteins and discover novel targets for ischemic heart disease (IHD) and other diseases.
Objectives
The purpose of this study was to examine associations of proteomics and genetics data with IHD in population studies to discover novel preventive treatments.
Methods
We conducted a nested case-cohort study in the China Kadoorie Biobank (CKB) involving 1,971 incident IHD cases and 2,001 subcohort participants who were genotyped and free of prior cardiovascular disease. We measured 1,463 proteins in the stored baseline samples using the OLINK EXPLORE panel. Cox regression yielded adjusted HRs for IHD associated with individual proteins after accounting for multiple testing. Moreover, cis-protein quantitative loci (pQTLs) identified for proteins in genome-wide association studies of CKB and of UK Biobank were used as instrumental variables in separate 2-sample Mendelian randomization (MR) studies involving global CARDIOGRAM+C4D consortium (210,842 IHD cases and 1,378,170 controls).
Results
Overall 361 proteins were significantly associated at false discovery rate <0.05 with risk of IHD (349 positively, 12 inversely) in CKB, including N-terminal prohormone of brain natriuretic peptide and proprotein convertase subtilisin/kexin type 9. Of these 361 proteins, 212 had cis-pQTLs in CKB, and MR analyses of 198 variants in CARDIOGRAM+C4D identified 13 proteins that showed potentially causal associations with IHD. Independent MR analyses of 307 cis-pQTLs identified in Europeans replicated associations for 4 proteins (FURIN, proteinase-activated receptor-1, Asialoglycoprotein receptor-1, and matrix metalloproteinase-3). Further downstream analyses showed that FURIN, which is highly expressed in endothelial cells, is a potential novel target and matrix metalloproteinase-3 a potential repurposing target for IHD.
Conclusions
Integrated analyses of proteomic and genetic data in Chinese and European adults provided causal support for FURIN and multiple other proteins as potential novel drug targets for treatment of IHD.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.3MB, Terms of use)
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- Publisher copy:
- 10.1016/j.jacc.2023.09.804
+ Wellcome Trust
More from this funder
- Grant:
- 104085/Z/14/Z
- 202922/Z/16/Z
- 212946/Z/18/Z
- 088158/Z/09/Z
+ Medical Research Council
More from this funder
- Grant:
- MC_UU_00017/1
- MC_PC_14135
- MC_UU_12026/2
- MC_U137686851
- MC_PC_13049
- Publisher:
- Elsevier
- Journal:
- Journal of the American College of Cardiology More from this journal
- Volume:
- 82
- Issue:
- 20
- Pages:
- 1906-1920
- Publication date:
- 2023-11-06
- Acceptance date:
- 2023-09-15
- DOI:
- EISSN:
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1558-3597
- ISSN:
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0735-1097
- Language:
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English
- Keywords:
- Pubs id:
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1541409
- Local pid:
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pubs:1541409
- Deposit date:
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2023-10-06
Terms of use
- Copyright holder:
- Mazidi et al
- Copyright date:
- 2023
- Rights statement:
- © 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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