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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.
journal contributionposted on 2017-11-24, 15:06 authored by Meixia Ren, Fu Liang Ng, Helen R. Warren, Kate Witkowska, Michael Baron, Zhilong Jia, Claudia Cabrera, Ruoxin Zhang, Borbala Mifsud, Patricia B. Munroe, Qingzhong Xiao, Andrea Townsend-Nicholson, Adrian J. Hobbs, Shu Ye, Mark J. Caulfield
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.
M.J.C., M.R., H.R.W., K.W., C.C., P.B.M. and B.M. are supported by the National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease at Barts. M.R. is the recipient of China Scholarship Council (No. 2011632047). F.L.N. is a British Heart Foundation Clinical Fellowship (FS/12/82/29736). S.Y. is supported by the British Heart Foundation (PG/16/9/31995 and RG/16/13/32609). This work falls under the portfolio of research conducted within the NIHR Leicester Biomedical Research Centre. This research has been conducted using the UK Biobank Resource. Funding to pay the Open Access publication charges for this article was provided by Queen Mary, University of London.
CitationHuman Molecular Genetics, 2017
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences
- VoR (Version of Record)