Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor 1 Gene Modulate Guanylate Cyclase Activity

Background: Human genetic variation in the NPR1 (natriuretic peptide receptor 1 gene, encoding NPR-A, atrial natriuretic peptide receptor 1) was recently shown to affect blood pressure (BP). NPR-A catalyzes the intracellular conversion of guanosine triphosphate to cGMP (cyclic 3,5-guanosine monophosphate) on binding of ANP, BNP (atrial or brain natriuretic peptide). Increased levels of cGMP decrease BP by inducing natriuresis, diuresis, and vasodilation. Methods: We performed a meta-analysis of low-frequency and rare NPR1 variants for BP association in up to 491584 unrelated individuals. To examine whether the identified BP-associated variants affect NPR-A function, the cGMP response to ANP and BNP was measured in cells expressing wild-type NPR1 and cells expressing the NPR1 variants. Results: In this study, we identified BP associations of 3 amino acid altering variants of NPR1. The minor alleles of rs35479618 (p.E967K, gnomAD non-Finnish European allele frequency 0.017) and rs116245325 (p.L1034F, allele frequency 0.0007) were associated with higher BP (P=4.0x10(-25) and P=9.9x10(-8), respectively), while the minor allele of rs61757359 (p.G541S, allele frequency 0.003) was associated with lower BP (P=1.8x10(-9)). Cells transiently expressing 967K or 1034F NPR-A displayed decreased cGMP production in response to ANP and BNP (all P<10(-6)), while cells expressing 541S NPR-A produced more cGMP compared with cells expressing wild-type NPR-A (P <= 4.13x10(-5) for ANP and P <= 4.24x10(-3) for BNP). Conclusions: In summary, the loss or gain of guanylate cyclase activity for these NPR1 allelic variants could explain the higher or lower BP observed for carriers in large population-based studies.