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

Area of Science:

• Genetics
• Cardiovascular Physiology

Background:

• Human genetic variation in the natriuretic peptide receptor 1 (NPR1) gene impacts blood pressure (BP).
• NPR-A, encoded by NPR1, is crucial for converting guanosine triphosphate to cyclic guanosine monophosphate (cGMP) upon binding of natriuretic peptides.
• Elevated cGMP levels reduce BP through natriuresis, diuresis, and vasodilation.

Purpose of the Study:

• To conduct a meta-analysis of low-frequency and rare NPR1 variants for BP association.
• To investigate whether identified BP-associated variants affect NPR-A function and cGMP production.

Main Methods:

• Meta-analysis of NPR1 variants for BP association in a large cohort (up to 491,584 individuals).
• Functional assays measuring cGMP response to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cells expressing wild-type NPR1 and identified variants.

Main Results:

• Identified three NPR1 variants associated with BP: rs35479618 (p.E967K) and rs116245325 (p.L1034F) linked to higher BP, and rs61757359 (p.G541S) linked to lower BP.
• Variants p.E967K and p.L1034F impaired NPR-A's guanylate cyclase activity, reducing cGMP production in response to ANP and BNP.
• Variant p.G541S enhanced NPR-A's guanylate cyclase activity, increasing cGMP production.

Conclusions:

• The identified NPR1 variants' impact on guanylate cyclase activity explains their association with altered blood pressure.
• These findings link specific genetic variations in NPR1 to blood pressure regulation through modulation of the cGMP pathway.