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Randomized Controlled Trial
. 2015 Feb;8(1):141-9.
doi: 10.1161/CIRCGENETICS.114.000624. Epub 2014 Dec 1.

Circulating atrial natriuretic peptide genetic association study identifies a novel gene cluster associated with stroke in whites

Naveen L Pereira  1 , Nirubol Tosakulwong  2 , Christopher G Scott  2 , Gregory D Jenkins  2 , Naresh Prodduturi  2 , Yubo Chai  2 , Timothy M Olson  2 , Richard J Rodeheffer  2 , Margaret M Redfield  2 , Richard M Weinshilboum  2 , John C Burnett  2
Affiliations
Randomized Controlled Trial

Circulating atrial natriuretic peptide genetic association study identifies a novel gene cluster associated with stroke in whites

Naveen L Pereira et al. Circ Cardiovasc Genet. 2015 Feb.

Abstract

Background: The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility.

Methods and results: Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP1-98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55±8% of wild-type protein (P=0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P<0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P=0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P=0.004).

Conclusions: This is the first large-scale genetic association study of circulating NT-proANP levels performed with replication and functional assessment that identified genetic variants in the MTHFR-CLCN6-NPPA-NPPB cluster to be significantly associated with NT-proANP levels. The clinical significance of this variation is related to lower NT-proANP levels, higher blood pressures, and an increased risk of stroke in the general community.

Keywords: atrial natriuretic factor; genetic association studies; heart failure; hypertension; stroke.

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Conflict of interest statement

Conflict of Interest Disclosures: None

Figures

Figure 1
Figure 1
Manhattan plot of the results of the large-scale genetic association study of circulating ANP levels in the general community. The red line represents a p value = 3.9 × 10−7, the level required for statistical significance.
Figure 2
Figure 2
Genetic associations with ANP concentrations across the chromosome 1 region of interest: Manhattan plot of −log10 (P values) from conditional logistic regression for observed (blue circle) and imputed (blue diamond) SNP genotypes according to their physical location. The recombination rate in centimorgan per megabase (blue line) and the linkage disequilibrium (r2) of each SNP with the rs5063 SNP are shown.
Figure 3
Figure 3
Atrial natriuretic peptide (NPPA) functional genomics: A. Western blot analysis showing NPPA wild-type (WT) protein expression as compared with rs5063 variant NPPA protein expression for constructs with nonsynonymous single-nucleotide polymorphisms expressed in HEK293 cells. EV denotes transfection with an empty vector. B. A dot plot with NPPA immunoreactive protein levels of rs5063 allozyme as compared to WT protein. Each dot represents independent transfection experiments. All values are corrected for transfection efficiency.
Figure 4
Figure 4
Kaplan-Meier curve demonstrating stroke free survival according to carrier status of the NPPA rs5063 genotype. Numbers below the figure represent the survival estimate (number at risk). P-value from Cox regression analysis including age and gender as covariates.
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