The Gene Encoding Atrial Natriuretic Peptide and the Risk of Human Stroke

<jats:p> <jats:italic>Background</jats:italic> —Recent evidence from an animal model of stroke, the stroke-prone spontaneously hypertensive rat, implicated the gene encoding atrial natriuretic peptide ( <jats:italic>ANP</jats:italic> ) as a possible candidate contributing to the likelihood of experiencing a stroke. The purpose of the present study was to investigate the role of <jats:italic>ANP</jats:italic> in the pathogenesis of cerebrovascular accidents in humans. </jats:p> <jats:p> <jats:italic>Methods and Results</jats:italic> —We investigated 2 previously known markers at <jats:italic>ANP</jats:italic> , <jats:italic>G1837A</jats:italic> and <jats:italic>T2238C</jats:italic> , for their possible association with the occurrence of stroke. This was the largest matched case-controlled sample studied thus far; the sample was drawn from a large prospective study (the Physician’s Health Study). When assuming a dominant mode of inheritance, a statistically significant positive association was observed for the <jats:italic>1837A</jats:italic> allele, indicating an odds ratio of 1.64 (95% confidence interval, 1.01 to 2.65) for stroke. This observation led to the discovery of a new molecular variant in exon 1, <jats:italic>G664A,</jats:italic> which was responsible for a valine-to-methionine substitution in the proANP peptide. This mutation, which was in linkage disequilibrium with the <jats:italic>G1837A</jats:italic> marker, was associated with the occurrence of stroke (odds ratio, 2.0; 95% confidence interval, 1.17 to 3.19; <jats:italic>P</jats:italic> =0.01). </jats:p> <jats:p> <jats:italic>Conclusions</jats:italic> —Our findings suggest that molecular variants of the ANP gene may represent an independent risk factor for cerebrovascular accidents in humans. The strong parallelism to the experimental data obtained in the stroke-prone animal model provides assurance for the relevance of our observation. </jats:p>