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The biological impact of blood pressure associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle

Ren, M; Ng, FL; Warren, H; Witkowska, K; Baron, M; Jia, Z; Cabrera, C; ... Caulfield, M; + view all (2017) The biological impact of blood pressure associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle. Human Molecular Genetics 10.1093/hmg/ddx375. (In press). Green open access

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Abstract

Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells and endothelial cells from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in vascular smooth muscle cells, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased vascular smooth muscle cell proliferation, angiotensin II-induced calcium flux, and cell contraction. However, an analogous genotype-dependent association was not observed in vascular endothelial cells. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention.

Type: Article
Title: The biological impact of blood pressure associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddx375
Publisher version: http://doi.org/10.1093/hmg/ddx375
Language: English
Additional information: Copyright © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Keywords: alleles hypertension electroconvulsive therapy calcium muscle, smooth, vascular chromatin genes genotype nuclear proteins single nucleotide polymorphism rna, messenger genetics natriuretic peptide receptor activity genome-wide association study epidural cortical stimulation biobanks
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/10031403
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