title: Atrial natriuretic peptide genetic variant rs5065 and risk for cardiovascular disease in the general community: a 9-year follow-up study.
abstract: We analyzed the phenotype associated with the atrial natriuretic peptide (ANP) genetic variant rs5065 in a random community-based sample. We also assessed and compared the biological action of 2 concentrations (10(-10) mol/L, 10(-8) mol/L) of ANP and ANP-RR, the protein variant encoded by the minor allele of rs5065, on activation of the guanylyl cyclase (GC)-A and GC-B receptors, production of the second messenger 3',5'-cGMP in endothelial cells, and endothelial permeability. rs5065 genotypes were determined in a cross-sectional adult cohort from Olmsted County, MN (n=1623). Genotype frequencies for rs5065 were 75%, 24%, and 1% for TT, TC, and CC, respectively. Multivariate analysis showed that the C allele was associated with increased risk of cerebrovascular accident (hazard ratio, 1.43; 95% confidence interval, 1.09-1.86; P=0.009) and higher prevalence of myocardial infarction (odds ratio, 1.82; 95% confidence interval, 1.07-3.09; P=0.026). ANP-RR 10(-8) mol/L activated the GC-A receptor (83.07±8.31 versus no treatment 0.18±0.04 per 6 wells; P=0.006), whereas ANP-RR 10(-10) mol/L did not. Neither 10(-8) mol/L nor 10(-10) mol/L ANP-RR activated GC-B receptor (P=0.10, P=0.35). ANP 10(-8) mol/L and ANP-RR 10(-8) mol/L stimulated 3',5'-cGMP production in endothelial cells similarly (P=0.58). Both concentrations of ANP-RR significantly enhanced human aortic endothelial cell permeability (69 versus 29 relative fluorescence units [RFUs], P=0.012; 58 versus 39 RFUs, P=0.015) compared with ANP. The minor allele of rs5065 was associated with increased cardiovascular risk. ANP-RR activated the GC-A receptor, increased 3',5'-cGMP in endothelial cells, and when compared with ANP, augmented endothelial cell permeability.
authors.affiliation: Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905. cannone.valentina@mayo.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cannone
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Huntley
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.forename: Denise M
authors.initials: DM
authors.lastname: Heublein
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Scott
authors.forename: Kent R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodeheffer
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000483:Alleles; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D010539:Permeability / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D050705:Receptors, Guanylate Cyclase-Coupled / Q000378:metabolism; D012306:Risk; D015290:Second Messenger Systems / Q000187:drug effects / Q000235:genetics
chemical_list: D009320:Atrial Natriuretic Factor; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP
keywords: atrial natriuretic peptides; cardiovascular diseases; natriuretic peptides; stroke
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