A functional genetic variant (N521D) in natriuretic peptide receptor 3 is associated with diastolic dysfunction: the prevalence of asymptomatic ventricular dysfunction study.
OBJECTIVE
To evaluate the impact of a functional genetic variant in the natriuretic peptide clearance receptor, NPR3, on circulating natriuretic peptides (NPs) and myocardial structure and function in the general community.


BACKGROUND
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 NPR3 nonsynonymous single nucleotide polymorphism (SNP) rs2270915, resulting in a N521D substitution in the intracellular catalytic domain that interacts with Gi could affect receptor function. Whether this SNP is associated with alterations in NPs levels and altered cardiac structure and function is unknown.


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 comprehensive echocardiography.


RESULTS
Genotype frequencies for rs2270915 were as follows: (A/A 60%, A/G 36%, G/G 4%). All analyses performed were for homozygotes G/G versus wild type A/A plus the heterozygotes A/G. 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). There was no significant difference in NPs levels between the 2 groups suggesting that the clearance function of the receptor was not affected.


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 natriuretic peptides.
Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Naveen L
NL
Pereira
Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Margaret M
MM
Redfield
Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
Christopher
C
Scott
Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
Nirubol
N
Tosakulwong
Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Timothy M
TM
Olson
Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
Kent R
KR
Bailey
Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Richard J
RJ
Rodeheffer
Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
John C
JC
Burnett
D000368:Aged; D019943:Amino Acid Substitution; D009320:Atrial Natriuretic Factor / Q000097:blood; D003971:Diastole; D015150:Echocardiography, Doppler; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000503:physiopathology; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008910:Minnesota / Q000453:epidemiology; D015999:Multivariate Analysis; D020097:Natriuretic Peptide, Brain / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000453:epidemiology / Q000503:physiopathology
D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C