Abstract
Introduction: The tissue renin-angiotensin system is implicated in the pathogenesis of coronary
artery disease (CAD). As locally synthesised aldosterone is a potential mediator of
CAD, we have sought an association of the −344T>C variant of the aldosterone synthase
(CYP11B2) gene with CAD events. Methods: Subjects comprised of the Second Northwick Park Heart Study (NPHSII), a prospective
study of unrelated, healthy middle-aged Caucasian males. CAD events were recorded
in 2490 subjects, and defined as a sudden cardiac death, myocardial infarction or
coronary artery revascularisation procedure. Mean follow-up was 10.8 years. Aldosterone
synthase genotype was determined in 2490 subjects. Power calculation suggests that
we have 80% power (at a significance level of 0.05) to detect a difference in hazard
ratio (HR) between homozygote groups of 0.45. Results: One hundred and eighty-seven CAD events were recorded in 2490 subjects. In the group
overall, CAD events were independent of genotype with adjusted hazard ratios being
1.00 versus 1.25 versus 0.80 for TT versus TC versus CC genotypes, respectively, P=0.07. Genotype interactions with smoking and blood pressure were sought. Whilst CAD
events were independent of genotype amongst non-smokers, CC genotype in smokers was
associated with a reduced risk HR 2.02 versus 2.28 versus 0.82 for TT versus TC versus
CC genotypes, P=0.05 (HR for TT + TC versus CC were 1.77 versus 0.67, P=0.02). This apparent interaction remained after adjustment for conventional risk
factors. No such interaction was found with blood pressure. Conclusions: Aldosterone synthase genotype is unrelated to overall CAD events risk. A possible
interaction with smoking requires confirmation.
Keywords
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References
- Levels of angiotensin and molecular biology of the tissue renin angiotensin systems.Regul. Pept. 1993; 43: 1-20
- Angiotensin II and the heart: on the intracrine renin-angiotensin system.Hypertension. 2000; 35: 1183-1188
- Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production.J. Renin. Angiotensin. Aldosterone. Syst. 2002; 3: 214-221
- Mineralocorticoids and cardiovascular diseases. Status of knowledge from experimental and clinical studies.Ital. Heart J. 2000; 1: 595-604
- Aldosterone: cardiovascular assault.Am. Heart J. 2002; 144: S2-S7
- Aldosterone and the heart: towards a physiological function?.Cardiovasc. Res. 1999; 43: 7-12
- Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation.J. Biol. Chem. 1998; 273: 4883-4891
- Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease.Am. J. Cardiol. 1995; 76: 1259-1265
- Remodeling of the rat right and left ventricles in experimental hypertension.Circ. Res. 1990; 67: 1355-1364
- The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.N. Engl. J. Med. 1999; 341: 709-717
- Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.N. Engl. J. Med. 2003; 348: 1309-1321
- Vascular inflammation and the renin-angiotensin system.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1257-1266
- Aldosterone and vascular damage.Curr. Hypertens. Rep. 2000; 2: 327-334
- Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin.J. Clin. Endocrinol. Metab. 1996; 81: 2797-2800
- Aldosterone inhibits nitric oxide synthesis in rat vascular smooth muscle cells induced by interleukin-1 beta.Eur. J. Pharmacol. 1995; 290: 69-73
- Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart.Endocrinology. 2002; 143: 4828-4836
- Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy.Clin. Sci. (Lond.). 2002; 103: 425-431
- Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure.J. Am. Coll. Cardiol. 2001; 37: 1228-1233
- Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension.Hypertens. Res. 1999; 22: 17-22
- Haplotype analysis of CYP11B2.Endocr. Res. 1995; 21: 437-442
- Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1.J. Mol. Endocrinol. 2002; 28: 125-135
- Genetic determination of plasma aldosterone levels in essential hypertension.Am. J. Hypertens. 1998; 11: 856-860
- Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function.Circulation. 1998; 97: 569-575
- Evaluation of the aldosterone synthase (CYP11B2) gene polymorphism in patients with myocardial infarction.Hypertension. 2000; 35: 704-709
- Analysis of promoter region polymorphism in the aldosterone synthase gene (CYP11B2) as a risk factor for myocardial infarction.Am. J. Hypertens. 2000; 13: 134-139
- Joint effects of an aldosterone synthase (CYP11B2) gene polymorphism and classic risk factors on risk of myocardial infarction.Circulation. 1999; 100: 2213-2218
- Smoking and aldosterone synthase polymorphism.Circulation. 2000; 102: E183
- The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men.Thromb. Haemost. 1995; 73: 82-86
Arterial Hypertension and Ischaemic Heart Disease. Preventative aspects: report of an expert committee. World Health Organ Tech Rep Ser 1962;231:3–28.
World Health Organisation Myocardial Infarction Community Registers. Public Health Eur 1976;5:157–64.
Prineas R, Crow R, Blackburn H, editors. The Minnesota code manual of electrocardiographic findings. Standards and procedures for measurements and classification. Boston: PSC Inc.; 1982.
- Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males.J. Intern. Med. 1998; 244: 11-18
- Renin-angiotensin-aldosterone system (RAAS) gene polymorphism as a risk factor of coronary in-stent restenosis.Yonsei. Med. J. 2002; 43: 461-472
- Aldosterone synthase (CYP11B2) polymorphisms and cardiovascular function.J. Steroid Biochem. Mol. Biol. 1999; 69: 409-412
- Enhanced activation of the renin-angiotensin-aldosterone system in chronic cigarette smokers: a study of monozygotic twin pairs discordant for smoking.Clin. Pharmacol. Ther. 1988; 44: 426-430
- Cigarette smoking in hypertensive patients. Blood pressure and endocrine responses.Am. J. Med. 1985; 78: 564-568
- Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2.Hypertension. 1999; 33: 703-707
- Structural analysis and evaluation of the aldosterone synthase gene in hypertension.Hypertension. 1998; 32: 198-204
- Aldosterone synthase (CYP11B2) −344 C/T polymorphism is associated with left ventricular structure in human arterial hypertension.J. Am. Coll. Cardiol. 2001; 37: 878-884
- Lack of association between a polymorphism of the aldosterone synthase gene and left ventricular structure.Circulation. 1999; 99: 2255-2260
- Carotid and femoral intima-media thickness in relation to three candidate genes in a Caucasian population.J. Hypertens. 2002; 20: 1551-1561
Article info
Publication history
Accepted:
January 21,
2004
Received in revised form:
December 30,
2003
Received:
November 17,
2003
Identification
Copyright
© 2004 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
