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 language | English |
---|---|
Pages (from-to) | 199-210 |
Number of pages | 12 |
Journal | Human Molecular Genetics |
Volume | 27 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2018 |
Externally published | Yes |