Aldosterone synthase gene (CYP11B2) promoter polymorphism as a risk factor for ischaemic stroke in Tunisian Arabs

Abstract

Introduction. We investigated the contribution of aldosterone synthase CYP11B2 polymorphism (C—344T) to the age-related changes in blood pressure in stroke patients.

Subjects and methods. Study subjects comprised 329 stroke patients (121 normotensive, 208 hypertensive) and 444 healthy controls. Genotyping was done by PCR-RFLP, and the contribution of CYP11B2 polymorphism to the risk of stroke was analysed by regression analysis.

Results. The T allele, and CT, TT, and CT + TT genotypes, independently of sex and age, were significantly associated with increased stroke risk. Varied distributions of CYP11B2 genotypes were noted among patients with respect to gender, age and hypertension status, being pronounced in hypertensive patients. Both systolic and diastolic blood pressure were positively correlated with the presence of T allele. Mean systolic and diastolic blood pressure were significantly higher among young (< 60 years) CT and TT genotype carriers. Regression analysis confirmed the positive association of CT and TT genotypes and systolic blood pressure, and the negative association of diastolic blood pressure with odds of stroke development. Taking normotensive patients as reference, regression analysis identified TT genotype, age and female gender to be independently associated with increased odds of stroke.

Conclusion. Compared to CC genotype, CT and TT CYP11B2 genotypes are independently associated with increased stroke index.

Keywords

aldosterone hypertension polymorphism stroke Tunisia

Get full access to this article

View all access options for this article.

References

Hankey GJ

Potential new risk factors for ischemic stroke: what is their potential?

Stroke 2006;37:2181-8.

Dichgans M. Genetics of ischaemic stroke. Lancet Neurol 2007;6:149-61.

Flossmann E. , Schulz UG , Rothwell PM Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 2004;35:212-27.

Wang X. , Cheng S. , Brophy VH et al.; RMS Stroke SNP Consortium. A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-α in nonhypertensive patients. Stroke 2009;40:683-95.

Jerrard-Dunne P. , Cloud G. , Hassan A. , Markus HS Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 2003;34:1364-9.

Schulz UG , Flossmann E. , Rothwell PM Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke 2004;35:819-24.

Emsley HC , Smith CJ , Tyrrell PJ , Hopkins SJ Inflammation in acute ischemic stroke and its relevance to stroke critical care. Neurocrit Care 2008;9:125-38.

Klungel OH , Kaplan RC , Heckbert SR et al. Control of blood pressure and risk of stroke among pharmacologically treated hypertensive patients. Stroke 2000 ;31:420-4.

van Rijn MJ , Bos MJ , Isaacs A. et al. Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology. J Neurol Neurosurg Psychiatry 2007;78:1083-7.

10.

Nakase T. , Mizuno T. , Harada S. et al. Angiotensinogen gene polymorphism as a risk factor for ischemic stroke. J Clin Neurosci 2007;14:943-7.

11.

Sokol SI , Portnay EL , Curtis JP et al. Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke. Neurology 2004;63:208-13.

12.

Mulatero P. , Caserta M. , Bertello C. et al. Aldosterone as an independent factor in cerebrovascular damage. Clin Exp Hypertens 2008;30:785-97.

13.

Vyssoulis GP , Karpanou EA , Tzamou VE et al. Aldosterone levels and stroke incidence in essential hypertensive patients. Int J Cardiol 2009;(In press).

14.

Rigsby CS , Cannady WE , Dorrance AM

Aldosterone: good guy or bad guy in cerebrovascular disease?

Trends Endocrinol Metab 2005;16:401-06.

15.

Osmond JM , Rigsby CS , Dorrance AM

Is the mineralocorticoid receptor a potential target for stroke prevention?

Clin Sci (Lond) 2008 ;114:37-47.

16.

Joffe HV , Adler GK Effect of aldosterone and mineralocorticoid receptor blockade on vascular inflammation. Heart Fail Rev 2005;10:31-7.

17.

Brenner D. , Labreuche J. , Pico F. et al.; GENIC Investigators. The renin-angiotensin-aldosterone system in cerebral small vessel disease. J Neurol 2008;255:993-1000.

18.

Keavney B. , Mayosi B. , Gaukrodger N. et al. Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion. J Clin Endocrinol Metab 2005;90:1072-7.

19.

White PC , Slutsker L. Haplotype analysis of CYP11B2. Endocr Res 1995;21:437-42.

20.

Davies E. , Holloway CD , Ingram MC et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2 . Hypertension 1999;33:703-07.

21.

Stella P. , Bigatti G. , Tizzoni L. et al. Association between aldosterone synthase (CYP11B2) polymorphism and left ventricular mass in human essential hypertension. J Am Coll Cardiol 2004;43:265-70.

22.

Mayosi BM , Keavney B. , Watkins H. , Farrall M. Measured haplotype analysis of the aldosterone synthase gene and heart size . Eur J Hum Genet 2003;11:395-401.

23.

Schunkert H. , Hengstenberg C. , Holmer SR et al. Lack of association between a polymorphism of the aldosterone synthase gene and left ventricular structure. Circulation 1999;99: 2255-60.

24.

Ortlepp JR , Breithardt O. , Ohme F. , Hanrath P. , Hoffmann R. Lack of association among five genetic polymorphisms of the renin-angiotensin system and cardiac hypertrophy in patients with aortic stenosis. Am Heart J 2001;141:671-6.

25.

Sookoian S. , Gianotti TF , Pirola CJ Role of the C-344T aldosterone synthase gene variant in left ventricular mass and left ventricular structure-related phenotypes . Heart 2008;94: 903-10.

26.

Sookoian S. , Gianotti TF , González CD , Pirola CJ Association of the C-344T aldosterone synthase gene variant with essential hypertension: a meta-analysis. J Hypertens 2007;25:5-13.

27.

Safar ME , Cattan V. , Lacolley P. et al. Aldosterone synthase gene polymorphism, stroke volume and age-related changes in aortic pulse wave velocity in subjects with hypertension. J Hypertens 2005;23:1159-66.

28.

Pojoga L. , Gautier S. , Blanc H. et al. Genetic determination of plasma aldosterone levels in essential hypertension. Am J Hypertens 1998;11:856-60.

29.

Tiret L. , Mallet C. , Poirier O. et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2000;35: 29-35.

30.

Brenner D. , Labreuche J. , Poirier O. , Cambien F. , Amarenco P. ; Genic Investigators. Renin-angiotensin-aldosterone system in brain infarction and vascular death. Ann Neurol 2005;58: 131-8.

31.

Takai E. , Akita H. , Kanazawa K. et al. Association between aldosterone synthase (CYP11B2) gene polymorphism and left ventricular volume in patients with dilated cardiomyopathy. Heart 2002;88:649-50.

32.

Hlubocká Z. , Jáchymová M. , Heller S. et al. Association of the -344T/C aldosterone synthase gene variant with essential hypertension . Physiol Res 2008;(In press).

33.

Russo P. , Loguercio M. , Lauria F. et al.; European Collaborative Group of the IMMIDIET Project. Age- and gender-dependent association of the -344C/T polymorphism of CYP11B2 with blood pressure in European populations. J Hum Hypertens 2007;21:333-6.

34.

Yamada Y. , Ando F. , Shimokata H. Association of gene polymorphisms with blood pressure and the prevalence of hypertension in community-dwelling Japanese individuals. Int J Mol Med 2007;19:675-83.

35.

Isaji M. , Mune T. , Takada N. et al. Correlation between left ventricular mass and urinary sodium excretion in specific genotypes of CYP11B2. J Hypertens 2005;23:1149-57.

36.

Kumar NN , Benjafield AV , Lin RC , Wang WY , Stowasser M. , Morfia BJ Haplotype analysis of aldosterone synthase gene CYP11B2 polymorphism shows association with essential hypertension. J Hypertens 2003;21:1331-7.

37.

Tamaki S. , Iwai N. , Tsujita Y. , Kinoshita M. Genetic polymorphism of CYP11B2 gene and hypertension in Japanese. Hypertension 1999;33:266-70.

38.

Gormley K. , Bevan S. , Markus HS Polymorphisms in genes of the renin-angiotensin system and cerebral small vessel disease. Cerebrovasc Dis 2007;23:148-55.