Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor 1 Gene Modulate Guanylate Cyclase Activity
| Autor: | Connie R. Bezzina, Sara Vandenwijngaert, Najim Lahrouchi, John L. Diener, Clara D. Ledsky, Daniel Bloch, Lisa Ames, Florian Wunderer, Toshiyuki Honda, Mohsin A.F. Khan, Christopher Newton-Cheh, Emmanuel S. Buys |
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| Přispěvatelé: | Cardiology, Graduate School, ACS - Heart failure & arrhythmias |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.drug_class Blood Pressure 030204 cardiovascular system & hematology Polymorphism Single Nucleotide 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Guanosine monophosphate medicine Natriuretic peptide Animals Humans Allele frequency Chemistry Guanylate cyclase activity Genetic Variation General Medicine Brain natriuretic peptide NPR1 Minor allele frequency 030104 developmental biology Endocrinology Guanylate Cyclase Hypertension Atrial natriuretic peptide receptor Receptors Atrial Natriuretic Factor |
| Zdroj: | Circulation. Genomic and precision medicine, 12(8). Lippincott Williams and Wilkins Ltd. |
| ISSN: | 2574-8300 |
| Popis: | 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 491 584 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 =4.0×10 −25 and P =9.9×10 −8 , respectively), while the minor allele of rs61757359 (p.G541S, allele frequency 0.003) was associated with lower BP ( P =1.8×10 −9 ). Cells transiently expressing 967K or 1034F NPR-A displayed decreased cGMP production in response to ANP and BNP (all P –6 ), while cells expressing 541S NPR-A produced more cGMP compared with cells expressing wild-type NPR-A ( P ≤4.13×10 −5 for ANP and P ≤4.24×10 −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. |
| Databáze: | OpenAIRE |
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