The FES Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis.
Karamanavi, Elisavet; McVey, David G; van der Laan, Sander W; Stanczyk, Paulina J; Morris, Gavin E; Wang, Yifan; Yang, Wei; Chan, Kenneth; Poston, Robin N; Luo, Jun; Zhou, Xinmiao; Gong, Peng; Jones, Peter D; Cao, Junjun; Kostogrys, Renata B; Webb, Tom R; Pasterkamp, Gerard; Yu, Haojie; Xiao, Qingzhong; Greer, Peter A; Stringer, Emma J; Samani, Nilesh J; Ye, Shu
(2022) Circulation research, volume 131, issue 12, pp. 1004 - 1017
(Article)
Abstract
BACKGROUND: Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of
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cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis. METHODS AND RESULTS: Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES. There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet. CONCLUSIONS: We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.
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Keywords: Animals, Arteries/metabolism, Atherosclerosis/genetics, Coronary Artery Disease/genetics, Genome-Wide Association Study, Humans, Mice, Myocytes, Smooth Muscle/metabolism, Plaque, Atherosclerotic/genetics, RNA/metabolism, atherosclerosis, coronary artery disease, monocytes, genetics, FES, Cardiology and Cardiovascular Medicine, Physiology, Journal Article
ISSN: 0009-7330
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: S.W. van der Laan received funding from Roche for unrelated work. The other authors report no conflicts. Funding Information: We are thankful for the support of the British Heart Foundation (PG/16/9/31995, RG/16/13/32609, PG/18/73/34059, SP/19/2/344612, and RG/19/9/34655), the National University of Singapore and the National University Health System Internal Grant Funding (NUHSRO/2022/004/Startup/01), the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20), the AI for Health working group of the EWUU alliance ( https://aiforhealth.ewuu.nl/ ), the European Research Area Network on Cardiovascular Diseases program (01KL1802), the Leducq Foundation, and the National Natural Science Foundation of China (81370202, 82070466, and 82000341). This work falls under the portfolio of research conducted within the National Institute for Health Research Leicester Biomedical Research Centre. Funding Information: We are thankful for the support of the British Heart Foundation (PG/16/9/31995, RG/16/13/32609, PG/18/73/34059, SP/19/2/344612, and RG/19/9/34655), the National University of Singapore and the National University Health System Internal Grant Funding (NUHSRO/2022/004/Startup/01), the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20), the AI for Health working group of the EWUU alliance (https://aiforhealth.ewuu.nl/), the European Research Area Network on Cardiovascular Diseases program (01KL1802), the Leducq Foundation, and the National Natural Science Foundation of China (81370202, 82070466, and 82000341). This work falls under the portfolio of research conducted within the National Institute for Health Research Leicester Biomedical Research Centre. Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved.
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