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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Elevated blood pressure (BP) is amajor 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 smoothmuscle cells (VSMCs) and endothelial cells (ECs) fromdifferent individuals, we found that the BP-elevating alleles within one linkage disequilibriumblock identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3mRNA 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, putativemechanisms 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.

Original languageEnglish
Pages (from-to)199-210
Number of pages12
JournalHuman Molecular Genetics
Volume27
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

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