Plasma Proteomics to Identify Drug Targets for Ischemic Heart Disease

Mohsen Mazidi; Neil Wright; Pang Yao; Christiana Kartsonaki; Iona Y Millwood; Hannah Fry; Saredo Said; Alfred Pozarickij; Pei Pei; Yiping Chen; Daniel Avery; Huaidong Du; Dan Valle Schmidt; Ling Yang; Jun Lv; Canqing Yu; Junshi Chen; Michael Hill; Michael V Holmes; Joanna M M Howson; Richard Peto; Rory Collins; Derrick A Bennett; Robin G Walters; Liming Li; Robert Clarke; Zhengming Chen; China Kadoorie Biobank Collaborative Group

doi:10.1016/j.jacc.2023.09.804

Plasma Proteomics to Identify Drug Targets for Ischemic Heart Disease

J Am Coll Cardiol. 2023 Nov 14;82(20):1906-1920. doi: 10.1016/j.jacc.2023.09.804.

Authors

Mohsen Mazidi¹, Neil Wright¹, Pang Yao¹, Christiana Kartsonaki², Iona Y Millwood², Hannah Fry², Saredo Said¹, Alfred Pozarickij¹, Pei Pei³, Yiping Chen², Daniel Avery¹, Huaidong Du², Dan Valle Schmidt¹, Ling Yang², Jun Lv⁴, Canqing Yu⁴, Junshi Chen⁵, Michael Hill², Michael V Holmes¹, Joanna M M Howson⁶, Richard Peto¹, Rory Collins¹, Derrick A Bennett², Robin G Walters², Liming Li⁴, Robert Clarke⁷, Zhengming Chen⁸; China Kadoorie Biobank Collaborative Group

Collaborators

China Kadoorie Biobank Collaborative Group:
Junshi Chen, Zhengming Chen, Robert Clarke, Rory Collins, Liming Li, Chen Wang, Jun Lv, Richard Peto, Robin Walters, Daniel Avery, Maxim Barnard, Derrick Bennett, Ruth Boxall, Sushila Burgess, Ka Hung Chan, Yiping Chen, Zhengming Chen, Johnathan Clarke, Robert Clarke, Huaidong Du, Ahmed Edris Mohamed, Hannah Fry, Simon Gilbert, Pek Kei Im, Andri Iona, Maria Kakkoura, Christiana Kartsonaki, Hubert Lam, Kuang Lin, James Liu, Mohsen Mazidi, Iona Millwood, Sam Morris, Qunhua Nie, Alfred Pozarickij, Paul Ryder, Saredo Said, Dan Schmidt, Becky Stevens, Iain Turnbull, Robin Walters, Baihan Wang, Lin Wang, Neil Wright, Ling Yang, Xiaoming Yang, Pang Yao, Xiao Han, Can Hou, Qingmei Xia, Chao Liu, Jun Lv, Pei, Dianjanyi Sun, Canqing Yu, Naying Chen, Duo Liu, Zhenzhu Tang, Ningyu Chen, Qilian Jiang, Jian Lan, Mingqiang Li, Yun Liu, Fanwen Meng, Jinhuai Meng, Rong Pan, Yulu Qin, Ping Wang, Sisi Wang, Liuping Wei, Liyuan Zhou, Caixia Dong, Pengfei Ge, Xiaolan Ren, Zhongxiao Li, Enke Mao, Tao Wang, Hui Zhang, Xi Zhang, Jinyan Chen, Ximin Hu, Xiaohuan Wang, Zhendong Guo, Huimei Li, Yilei Li, Min Weng, Shukuan Wu, Shichun Yan, Mingyuan Zou, Xue Zhou, Ziyan Guo, Quan Kang, Yanjie Li, Bo Yu, Qinai Xu, Liang Chang, Lei Fan, Shixian Feng, Ding Zhang, Gang Zhou, Yulian Gao, Tianyou He, Pan He, Chen Hu, Huarong Sun, Xukui Zhang, Biyun Chen, Zhongxi Fu, Yuelong Huang, Huilin Liu, Qiaohua Xu, Li Yin, Huajun Long, Xin Xu, Hao Zhang, Libo Zhang, Jian Su, Ran Tao, Ming Wu, Jie Yang, Jinyi Zhou, Yonglin Zhou, Yihe Hu, Yujie Hua, Jianrong Jin, Fang Liu, Jingchao Liu, Yan Lu, Liangcai Ma, Aiyu Tang, Jun Zhang, Liang Cheng, Ranran Du, Ruqin Gao, Feifei Li, Shanpeng Li, Yongmei Liu, Feng Ning, Zengchang Pang, Xiaohui Sun, Xiaocao Tian, Shaojie Wang, Yaoming Zhai, Hua Zhang, Wei Hou, Silu Lv, Junzheng Wang, Xiaofang Chen, Xianping Wu, Ningmei Zhang, Weiwei Zhou, Xiaofang Chen, Jianguo Li, Jiaqiu Liu, Guojin Luo, Qiang Sun, Xunfu Zhong, Weiwei Gong, Ruying Hu, Hao Wang, Meng Wang, Min Yu, Lingli Chen, Qijun Gu, Dongxia Pan, Chunmei Wang, Kaixu Xie, Xiaoyi Zhang

Affiliations

¹ Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
² Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Medical Research Council Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
³ Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China.
⁴ Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China; Key Laboratory of Epidemiology of Major (Peking University), Ministry of Education, Beijing, China.
⁵ China National Center for Food Risk Assessment, Beijing, China.
⁶ Novo Nordisk Research Centre, Oxford, United Kingdom.
⁷ Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. Electronic address: robert.clarke@ndph.ox.ac.uk.
⁸ Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Medical Research Council Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. Electronic address: zhengming.chen@ndph.ox.ac.uk.

Abstract

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.

Keywords: Mendelian randomization; diverse populations; drug target; genetics; ischemic heart disease; plasma proteomics; prospective studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Case-Control Studies
Cohort Studies
Endothelial Cells
Furin*
Genome-Wide Association Study
Humans
Matrix Metalloproteinases
Myocardial Ischemia* / drug therapy
Myocardial Ischemia* / epidemiology
Myocardial Ischemia* / genetics
Prospective Studies
Proteomics
Risk Factors

Substances

Furin
Matrix Metalloproteinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding