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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

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-w...

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Autores principales: Ren, Meixia, Ng, Fu Liang, Warren, Helen R, Witkowska, Kate, Baron, Michael, Jia, Zhilong, Cabrera, Claudia, Zhang, Ruoxin, Mifsud, Borbala, Munroe, Patricia B, Xiao, Qingzhong, Townsend-Nicholson, Andrea, Hobbs, Adrian J, Ye, Shu, Caulfield, Mark J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886068/
https://www.ncbi.nlm.nih.gov/pubmed/29040610
http://dx.doi.org/10.1093/hmg/ddx375
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author Ren, Meixia
Ng, Fu Liang
Warren, Helen R
Witkowska, Kate
Baron, Michael
Jia, Zhilong
Cabrera, Claudia
Zhang, Ruoxin
Mifsud, Borbala
Munroe, Patricia B
Xiao, Qingzhong
Townsend-Nicholson, Andrea
Hobbs, Adrian J
Ye, Shu
Caulfield, Mark J
author_facet Ren, Meixia
Ng, Fu Liang
Warren, Helen R
Witkowska, Kate
Baron, Michael
Jia, Zhilong
Cabrera, Claudia
Zhang, Ruoxin
Mifsud, Borbala
Munroe, Patricia B
Xiao, Qingzhong
Townsend-Nicholson, Andrea
Hobbs, Adrian J
Ye, Shu
Caulfield, Mark J
author_sort Ren, Meixia
collection PubMed
description 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.
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spelling pubmed-58860682018-04-09 The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle Ren, Meixia Ng, Fu Liang Warren, Helen R Witkowska, Kate Baron, Michael Jia, Zhilong Cabrera, Claudia Zhang, Ruoxin Mifsud, Borbala Munroe, Patricia B Xiao, Qingzhong Townsend-Nicholson, Andrea Hobbs, Adrian J Ye, Shu Caulfield, Mark J Hum Mol Genet Association Studies Article 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. Oxford University Press 2018-01-01 2017-10-10 /pmc/articles/PMC5886068/ /pubmed/29040610 http://dx.doi.org/10.1093/hmg/ddx375 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ 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
spellingShingle Association Studies Article
Ren, Meixia
Ng, Fu Liang
Warren, Helen R
Witkowska, Kate
Baron, Michael
Jia, Zhilong
Cabrera, Claudia
Zhang, Ruoxin
Mifsud, Borbala
Munroe, Patricia B
Xiao, Qingzhong
Townsend-Nicholson, Andrea
Hobbs, Adrian J
Ye, Shu
Caulfield, Mark J
The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
title The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
title_full The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
title_fullStr The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
title_full_unstemmed The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
title_short The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle
title_sort biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor c gene on human vascular smooth muscle
topic Association Studies Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886068/
https://www.ncbi.nlm.nih.gov/pubmed/29040610
http://dx.doi.org/10.1093/hmg/ddx375
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