Abstract 16669: Genetic Variation in the Natriuretic Peptide Clearance Receptor is Associated With Diastolic Dysfunction in the General Community
Background: The natriuretic peptide (NP) clearance receptor, NPR3, plays an important role in the clearance of NPs and through direct signaling mechanisms modulates smooth muscle cell function and cardiac fibroblast proliferation. A well-validated NPR3 nonsynonymous single nucleotide polymorphism (SNP) rs2270915, resulting in a N521D substitution in the intracellular domain, has been associated with hypertension. The objective of this study was to evaluate whether this SNP is associated with alterations in circulating NPs levels and altered cardiac structure and function.
Methods: DNA samples of 1931 randomly selected residents of Olmsted County, Minnesota were genotyped. Plasma NT-proANP1-98, ANP1-28, proBNP1-108, NT-proBNP1-76, BNP1-32 and BNP3-32 levels were measured. All subjects underwent echocardiography. Diastolic dysfunction was based on a composite of the ratio of mitral peak early filling velocity with velocity at atrial contraction (E/A), delta E/A with Valsalva, ratio of E with velocity of mitral annulus early diastolic motion (E/e’), E velocity deceleration time, pulmonary venous systolic and diastolic forward flows, A duration and pulmonary venous atrial reversal flow.
Results: Genotype frequencies for rs2270915 were as follows: (A/A 60%, n=1153, A/G 36%, n=702, G/G 4%, n=76). All analyses performed were for homozygotes G/G versus wild type A/A plus the heterozygotes A/G. There was no significant difference in plasma ANP (p=0.47), BNP1-32 (p=0.25), NT-proANP1-98 (p=0.53), proBNP1-108 (p=0.10) and NT-proBNP1-76 levels (p=0.18) between the 2 groups suggesting that the clearance function of the receptor was not affected. Diastolic dysfunction was significantly more common (p=0.007) in the homozygotes G/G (43%) than the A/A+A/G (28%) group. Multivariate regression adjusted for age, sex, body mass index and hypertension demonstrated rs2270915 to be independently associated with diastolic dysfunction (odds ratio 1.94, p=0.03).
Conclusions: A nonsynonymous NPR3 SNP is independently associated with diastolic dysfunction and this association does not appear to be related to alterations in circulating levels of NPs. The role of NPR3 in the pathophysiology of diastolic dysfunction needs to be further explored.
- © 2013 by American Heart Association, Inc.