This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rubattu, S. Articles by Lindpaintner, K. Search for Related Content PubMed PubMed Citation Articles by Rubattu, S. Articles by Lindpaintner, K. Related Collections Acute Stroke Syndromes Genetics of Stroke Risk Factors for Stroke

(Circulation. 1999;100:1722-1726.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

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

Speranza Rubattu, MD; Paul Ridker, MD, MPH; Meir J. Stampfer, MD; Massimo Volpe, MD; Charles H. Hennekens, MD, DrPH; Klaus Lindpaintner, MD

From the Divisions of Preventive Medicine (P.R., C.H.H.), Cardiovascular Diseases (S.R., P.R., K.L.), and the Channing Laboratory (M.J.S.), Department of Medicine, Brigham and Women's Hospital; the Department of Cardiology, Children's Hospital (K.L.); the Department of Ambulatory Care and Prevention, Harvard Medical School (C.H.H.); and the Departments of Epidemiology (M.J.S., C.H.H.) and Nutrition (M.J.S.), Harvard School of Public Health, Boston, Mass; the Department of Experimental Medicine and Pathology, La Sapienza University (S.R., M.V.), Rome, and Istituto Neurologico Mediterraneo Neuromed (S.R., M.V.), Pozzilli, Italy; and the Max Delbrück Centre for Molecular Medicine (K.L.), Berlin, Germany.

Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail kl{at}calvin.bwh.harvard.edu

Background—Recent evidence from an animal model of stroke, the stroke-prone spontaneously hypertensive rat, implicated the gene encoding atrial natriuretic peptide (ANP) as a possible candidate contributing to the likelihood of experiencing a stroke. The purpose of the present study was to investigate the role of ANP in the pathogenesis of cerebrovascular accidents in humans.

Methods and Results—We investigated 2 previously known markers at ANP, G1837A 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 Study). When assuming a dominant mode of inheritance, a statistically significant 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, G664A, which was responsible for a valine-to-methionine substitution in the proANP peptide. This mutation, which was in linkage disequilibrium with the G1837A 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 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.

Key Words: cerebrovascular disorders • genetics • natriuretic peptides

This article has been cited by other articles:

				C. Vassalle and M. G. Andreassi Genetic Polymorphisms of the Natriuretic Peptide System in the Pathogenesis of Cardiovascular Disease: What Lies on the Horizon? Clin. Chem., May 1, 2009; 55(5): 878 - 887. [Abstract] [Full Text] [PDF]

				C. Vassalle, M. G. Andreassi, C. Prontera, M. Fontana, L. Zyw, C. Passino, and M. Emdin Influence of ScaI and Natriuretic Peptide (NP) Clearance Receptor Polymorphisms of the NP System on NP Concentration in Chronic Heart Failure Clin. Chem., November 1, 2007; 53(11): 1886 - 1890. [Abstract] [Full Text] [PDF]

				P. De Paolis, V. Nobili, A. Lombardi, D. Tarasi, D. Barbato, S. Marchitti, U. Ganten, E. Brunetti, M. Volpe, and S. Rubattu Role of a Molecular Variant of Rat Atrial Natriuretic Peptide Gene in Vascular Remodeling Ann. Clin. Lab. Sci., January 1, 2007; 37(2): 135 - 140. [Abstract] [Full Text] [PDF]

				S. Rubattu, N. Hubner, U. Ganten, A. Evangelista, R. Stanzione, E. D. Angelantonio, R. Plehm, R. Langanki, E. Gianazza, L. Sironi, et al. Reciprocal congenic lines for a major stroke QTL on rat chromosome 1 Physiol Genomics, October 11, 2006; 27(2): 108 - 113. [Abstract] [Full Text] [PDF]

				S. Rubattu, G. Bigatti, A. Evangelista, C. Lanzani, R. Stanzione, L. Zagato, P. Manunta, S. Marchitti, V. Venturelli, G. Bianchi, et al. Association of Atrial Natriuretic Peptide and Type A Natriuretic Peptide Receptor Gene Polymorphisms With Left Ventricular Mass in Human Essential Hypertension J. Am. Coll. Cardiol., August 1, 2006; 48(3): 499 - 505. [Abstract] [Full Text] [PDF]

				N. Hubner, C. Yagil, and Y. Yagil Novel Integrative Approaches to the Identification of Candidate Genes in Hypertension Hypertension, January 1, 2006; 47(1): 1 - 5. [Abstract] [Full Text] [PDF]

				S. Rubattu, R. Stanzione, E. Di Angelantonio, B. Zanda, A. Evangelista, D. Tarasi, B. Gigante, A. Pirisi, E. Brunetti, and M. Volpe Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans Stroke, April 1, 2004; 35(4): 814 - 818. [Abstract] [Full Text] [PDF]

				T. J. Wang, M. G. Larson, D. Levy, E. J. Benjamin, E. P. Leip, T. Omland, P. A. Wolf, and R. S. Vasan Plasma Natriuretic Peptide Levels and the Risk of Cardiovascular Events and Death N. Engl. J. Med., February 12, 2004; 350(7): 655 - 663. [Abstract] [Full Text] [PDF]

				R. Y.L. Zee, D. Bates, and P. M. Ridker A Prospective Evaluation of the CD14 and CD18 Gene Polymorphisms and Risk of Stroke Stroke, April 1, 2002; 33(4): 892 - 895. [Abstract] [Full Text] [PDF]

				U. Guerrini, L. Sironi, E. Tremoli, M. Cimino, B. Pollo, A. M. Calvio, R. Paoletti, and M. Asdente New Insights Into Brain Damage in Stroke-Prone Rats: A Nuclear Magnetic Imaging Study Stroke, March 1, 2002; 33(3): 825 - 830. [Abstract] [Full Text] [PDF]

				A. Hassan, N. Ali, Y. Dong, N. D. Carter, and H. S. Markus Atrial natriuretic peptide gene G664A polymorphism and the risk of ischemic cerebrovascular disease Neurology, November 13, 2001; 57(9): 1726 - 1728. [Abstract] [Full Text] [PDF]

				D. L Vesely Atrial natriuretic peptides in pathophysiological diseases Cardiovasc Res, September 1, 2001; 51(4): 647 - 658. [Full Text] [PDF]

				G.J. Hademenos, M.J. Alberts, I. Awad, M. Mayberg, T. Shephard, A. Jagoda, R.E. Latchaw, H.W. Todd, K. Viste, R. Starke, et al. Advances in the genetics of cerebrovascular disease and stroke Neurology, April 24, 2001; 56(8): 997 - 1008. [Abstract] [Full Text] [PDF]

				L. Sironi, E. Tremoli, I. Miller, U. Guerrini, A. M. Calvio, I. Eberini, M. Gemeiner, M. Asdente, R. Paoletti, and E. Gianazza Acute-Phase Proteins Before Cerebral Ischemia in Stroke-Prone Rats : Identification by Proteomics Stroke, March 1, 2001; 32(3): 753 - 760. [Abstract] [Full Text] [PDF]

				A. Hassan and H. S. Markus Genetics and ischaemic stroke Brain, September 1, 2000; 123(9): 1784 - 1812. [Abstract] [Full Text] [PDF]

				S. Rubattu, M. A. Lee-Kirsch, P. DePaolis, R. Giliberti, B. Gigante, A. Lombardi, M. Volpe, and K. Lindpaintner Altered Structure, Regulation, and Function of the Gene Encoding the Atrial Natriuretic Peptide in the Stroke-Prone Spontaneously Hypertensive Rat Circ. Res., November 12, 1999; 85(10): 900 - 905. [Abstract] [Full Text] [PDF]