The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle. (10th October 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Human molecular genetics. Volume 27:Number 1(2018:Jan. 01)
• Page Start: 199
• Page End: 210
• Publication Date: 2017-10-10
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddx375
• Languages: English
• ISSNs: 0964-6906

Abstract

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.