Background-Recent evidence from an animal model of stroke, the stroke-prone
spontaneously hypertensive rat, implicated the gene encoding atrial natriu
retic peptide (AMP) as a possible candidate contributing to the likelihood
of experiencing a stroke. The purpose of the present study was to investiga
te the role of ANP in the pathogenesis of cerebrovascular accidents in huma
ns.
Methods and Results-We investigated 2 previously known markers at ANP, G183
7A and T2238C, 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 St
udy). When assuming a dominant mode of inheritance, a statistically signifi
cant positive association was observed for the 1837A 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, G66
4A, which was responsible for a valine-to-methionine substitution in the pr
oANP peptide. This mutation, which was in linkage disequilibrium with the G
1837A marker, was associated with the occurrence of stroke (odds ratio, 2.0
; 95% confidence interval, 1.17 to 3.19: P=0.01).
Conclusions-Our findings suggest that molecular variants of the ANP-gene ma
y represent an independent risk factor for cerebrovascular accidents in hum
ans. The strong parallelism to the experimental data obtained in the stroke
-prone animal model provides assurance for the relevance of our observation
.