Ren, M;
Ng, FL;
Warren, HR;
Witkowska, K;
Baron, M;
Jia, Z;
Cabrera, C;
Zhang, R;
Mifsud, B;
Munroe, PB;
et al.
Ren, M; Ng, FL; Warren, HR; Witkowska, K; Baron, M; Jia, Z; Cabrera, C; Zhang, R; Mifsud, B; Munroe, PB; Xiao, Q; Townsend-Nicholson, A; Hobbs, AJ; Ye, S; Caulfield, MJ
(2018)
The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle.
Hum Mol Genet, 27 (1).
pp. 199-210.
ISSN 1460-2083
https://doi.org/10.1093/hmg/ddx375
SGUL Authors: Ng, Fu Liang
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 (VSMCs) and endothelial cells (ECs) 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 VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. 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.
Item Type: |
Article
|
Additional Information: |
© 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: |
Blood Pressure, Databases, Nucleic Acid, Endothelial Cells, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Hypertension, Linkage Disequilibrium, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Polymorphism, Single Nucleotide, Receptors, Atrial Natriuretic Factor, Signal Transduction, Muscle, Smooth, Vascular, Endothelial Cells, Myocytes, Smooth Muscle, Humans, Hypertension, Receptors, Atrial Natriuretic Factor, Signal Transduction, Blood Pressure, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Databases, Nucleic Acid, Genetic Variation, Genome-Wide Association Study, Genetics & Heredity, 06 Biological Sciences, 11 Medical and Health Sciences |
SGUL Research Institute / Research Centre: |
Academic Structure > Institute of Medical & Biomedical Education (IMBE) |
Journal or Publication Title: |
Hum Mol Genet |
ISSN: |
1460-2083 |
Language: |
eng |
Dates: |
Date | Event |
---|
1 January 2018 | Published | 10 October 2017 | Published Online | 30 September 2017 | Accepted |
|
Publisher License: |
Creative Commons: Attribution-Noncommercial 4.0 |
Projects: |
|
PubMed ID: |
29040610 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/112396 |
Publisher's version: |
https://doi.org/10.1093/hmg/ddx375 |
Statistics
Item downloaded times since 18 Sep 2020.
Actions (login required)
![Edit Item](/style/images/action_view.png) |
Edit Item |