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(Stroke. 2004;35:814.)
© 2004 American Heart Association, Inc.

Original Contributions

Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans

Speranza Rubattu, MD; Rosita Stanzione, PhD; Emanuele Di Angelantonio, MD; Bastianina Zanda, MD; Anna Evangelista, BS; David Tarasi, MD; Bruna Gigante, MD; Angelo Pirisi, MD; Ercole Brunetti, MD Massimo Volpe, MD

From IRCCS Neuromed, Pozzilli (S.R., R.S., A.E., M.V.); Cardiology Division, Second Faculty of Medicine, University La Sapienza, Rome (S.R., D.T., M.V.); Clinica Neurologica, University of Sassari, Sassari (B.Z., A.P.); Department of Internal Medicine, First Faculty of Medicine, University La Sapienza, Rome (E.D.A.); Research Center, St Peter Hospital AFAR Fatebenefratelli, Rome (E.B.); and Biogem Scacl c/o IGB A. Buzzati-Traverso, Naples (B.G.), Italy.

Correspondence to Speranza Rubattu, MD, IRCCS Neuromed, Localitá Camerelle, 86077 Pozzilli, Italy. E-mail rubattu.speranza{at}neuromed.it

Background and Purpose— A precise definition of genetic factors responsible for common forms of stroke is still lacking. The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans’ susceptibility to develop ischemic stroke.

Methods— Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls).

Results— A significant association between the ANP/TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP/CC2238 genotype compared with cases carrying the ANP/TT2238 genotype (P=0.04). No direct association of NPRA with stroke occurrence was detected. However, a significant epistatic interaction between the ANP/CC2238 genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4).

Conclusions— Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found.

Key Words: cerebrovascular disorders • gene mutation • genetics • natriuretic peptides, atrial • receptors, atrial natriuretic factor

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