Atrial natriuretic peptide genetic variant rs5065 and risk for cardiovascular disease in the general community: A 9-year follow-up study

Valentina Cannone, Brenda K. Huntley, Timothy Mark Olson, Denise M. Heublein, Christopher G. Scott, Kent R Bailey, Margaret May Redfield, Richard J. Rodeheffer, John C Jr. Burnett

Research output: Contribution to journalArticle

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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 mol/L, 10 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 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 mol/L did not. Neither 10 mol/L nor 10 mol/L ANP-RR activated GC-B receptor (P=0.10, P=0.35). ANP 10 mol/L and ANP-RR 10 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.

Original languageEnglish (US)
Pages (from-to)860-865
Number of pages6
JournalHypertension
Volume62
Issue number5
DOIs
StatePublished - Nov 2013

Fingerprint

Atrial Natriuretic Factor
Cardiovascular Diseases
Endothelial Cells
Permeability
Alleles
Fluorescence
Genotype
Confidence Intervals
Second Messenger Systems
Multivariate Analysis
Stroke
Odds Ratio
Myocardial Infarction
Phenotype

Keywords

  • atrial natriuretic peptides
  • cardiovascular diseases
  • natriuretic peptidesstroke

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

Cite this

Atrial natriuretic peptide genetic variant rs5065 and risk for cardiovascular disease in the general community : A 9-year follow-up study. / Cannone, Valentina; Huntley, Brenda K.; Olson, Timothy Mark; Heublein, Denise M.; Scott, Christopher G.; Bailey, Kent R; Redfield, Margaret May; Rodeheffer, Richard J.; Burnett, John C Jr.

In: Hypertension, Vol. 62, No. 5, 11.2013, p. 860-865.

Research output: Contribution to journalArticle

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AU - Olson, Timothy Mark

AU - Heublein, Denise M.

AU - Scott, Christopher G.

AU - Bailey, Kent R

AU - Redfield, Margaret May

AU - Rodeheffer, Richard J.

AU - Burnett, John C Jr.

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AB - 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 mol/L, 10 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 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 mol/L did not. Neither 10 mol/L nor 10 mol/L ANP-RR activated GC-B receptor (P=0.10, P=0.35). ANP 10 mol/L and ANP-RR 10 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.

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