Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/42665
Title: Influence of a Coronary Artery Disease-Associated Genetic Variant on FURIN Expression and Effect of Furin on Macrophage Behavior.
Authors: Zhao, Guojun
Yang, Wei
Wu, Jingchun
Chen, Bairu
Yang, Xu
Chen, Junhui
McVey, David G.
Andreadi, Catherine
Gong, Peng
Webb, Tom R.
Samani, Nilesh J.
Ye, Shu
First Published: 5-Jul-2018
Publisher: American Heart Association, Lippincott, Williams & Wilkins
Citation: Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:1837-1844
Abstract: OBJECTIVE: Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. APPROACH AND RESULTS: A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele. An analysis of isogenic monocyte cell lines created by CRISPR-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. CONCLUSIONS: Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk.
DOI Link: 10.1161/ATVBAHA.118.311030
ISSN: 1079-5642
eISSN: 1524-4636
Links: https://www.ahajournals.org/doi/10.1161/ATVBAHA.118.311030
http://hdl.handle.net/2381/42665
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Description: The online-only Data Supplement is available with this article at https://www.ahajournals.org/journal/atvb/doi/suppl/10.1161/atvbaha.118.311030.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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