Circulating Atrial Natriuretic Peptide Genetic Association Study Identifies a Novel Gene Cluster Associated With Stroke in Whites. (February 2015)

• Record Type: Journal Article
• Authors: Pereira, Naveen L.; Tosakulwong, Nirubol; Scott, Christopher G.; Jenkins, Gregory D.; Prodduturi, Naresh; Chai, Yubo; Olson, Timothy M.; Rodeheffer, Richard J.; Redfield, Margaret M.; Weinshilboum, Richard M.; Burnett, John C.
• Is Part Of: Circulation. Volume 8:Number 1(2015)
• Publication Date: 2015-02
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000624
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP<sub>1–98</sub> concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the <italic>MTHFR-CLCN6-NPPA-NPPB</italic> 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 <italic>NPPA</italic> 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 (<italic>P</italic>=0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; <italic>P</italic><0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; <italic>P</italic>=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; <italic>P</italic>=0.004).</p> </sec> <sec> <title>Conclusions—</title> <p>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 <italic>MTHFR-CLCN6-NPPA-NPPB</italic> 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.</p> </sec> </abstract>