Proteome-Wide Genetic Study in East Asians and Europeans Identified Multiple Therapeutic Targets for Ischemic Stroke

作者：Pang Yao, Mohsen Mazidi, Alfred Pozarickij, Andri Iona, Neil Wright, Kuang Lin, Iona Y. Millwood, Hannah Fry, Christiana Kartsonaki, Yiping Chen, Ling Yang, Huaidong Du, Daniel Avery, Dan Schmidt, Dianjianyi Sun, Pei Pei, Jun Lv, Canqing Yu, Michael Hill, Derrick Bennett, Robin G. Walters, Liming Li, Robert Clarke, Zhengming Chen, Junshi Chen, Rory Collins, Chen Wang, Richárd Pető, Ruth Boxall, Sushila Burgess, Ka Hung Chan, Johnathan Clarke, Ahmed Edris Mohamed, Simon Gilbert, Pek Kei Im, Maria Kakkoura, Hubert Lam, James H. Liu, Sam Morris, Qunhua Nie, Paul Ryder, Saredo Said, Becky Stevens, Iain Turnbull, Baihan Wang, Lin Wang, Xiaoming Yang, Xiao Han, Can Hou, Qingmei Xia, Chao Liu, Pei Pei, Dianjanyi Sun, Naying Chen, Duo Liu, Zhenzhu Tang, Ningyu Chen, Qilian Jiang, Jian Lan, Mingqiang Li, Mingqiang Li, 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, Huimei Li, Min Weng, Shukuan Wu, Shichun Yan, Mingyuan Zou, Xuedong Zhou, Ziyan Guo, Quan Kang, Yanjie Li, Bo Yu, Qinai Xu, Liang Chang, Lei Fan, Shixian Feng, Ding Zhang, Gang Zhou, Yulian Gao, Tian-You 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, Shanpeng Li, Feng Ning, Zengchang Pang, Xiaohui Sun, Xiaocao Tian, Shaojie Wang, Yaoming Zhai, Hua Zhang, Licang CDC, Wei Hou, Silu Lv, Junzheng Wang, Xiaofang Chen, Xianping Wu, Ningmei Zhang, Weiwei Zhou, Xiaofang Chen, Jianguo Li, Jianguo Li, 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 · 发表于：Stroke · 年份：2025 · DOI：10.1161/strokeaha.125.050982 · 被引用次数：10 · 研究领域：Genetic Associations and Epidemiology、Genomics and Rare Diseases、Blood Coagulation and Thrombosis Mechanisms

BACKGROUND: Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke. METHODS: We extracted individual cis -protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established ≈20 years ago. These cis -protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22 664 cases) and Europeans (n=62 100 cases). We further undertook colocalization analyses to examine the shared causal variants of cis -protein quantitative trait locus with stroke, along with various downstream analyses (eg, phenome-wide association study, drug development lookups) to clarify mechanisms of action and druggability. RESULTS: In Mendelian randomization analyses, the genetically predicted plasma levels of 10 proteins were significantly associated with IS in East Asians (n=2) and Europeans (n=9), with 6 proteins (FGF5 [fibroblast growth factor 5], TMPRSS5 [transmembrane protease serine 5], FURIN, F11 [coagulation factor XI], ALDH2 [aldehyde dehydrogenase 2], and ABO [histo-blood group ABO system transferase]) showing positive and 4 (GRK5 [G protein-coupled receptor kinase 5], KIAA0319 [dyslexia-associated protein KIAA0319], PROCR [endothelial protein C receptor], and MMP12 [macrophage metalloelastase 12...