Circulating Atrial Natriuretic Peptide Genetic Association Study Identifies a Novel Gene Cluster Associated With Stroke in Whites

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