(Hypertension. 1999;34:423-429.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Genotype-Phenotype Relationships for the Renin-Angiotensin-Aldosterone System in a Normal Population
From INSERM U489, Hôpital Tenon (F.P., D.C., S.C., R.A.); INSERM U525, Hôpital Saint-Louis (E.B., F.S.); INSERM U337 (A.B.); and Investigation Préventive et Clinique (F.T.), Paris, France.
Correspondence to Florent Soubrier, INSERM U 525, Hôpital Saint-Louis, 1, Av Claude Vellefaux, 75475 Paris cedex 10. E-mail soubrier{at}inserm.chu-stlouis.fr
Abstract—The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I–converting enzyme (ACE) gene [4656(CT)2/3], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. Bmax and KD values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT)2/3 variant with plasma ACE levels was observed (P<0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (P=0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (P=0.02). No genotype effect of the AT1R A1166C polymorphism was detected either on the Bmax or the KD value of the Ang II receptors on platelets.
Key Words: angiotensinogen • angiotensin-converting enzyme • angiotensin II • aldosterone • polymorphism • blood pressure
This article has been cited by other articles:
 |
|
 |
|
  J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function Endocr. Rev., April 1, 2008; 29(2): 133 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J Milionis, M. S Kostapanos, K. Vakalis, I. Theodorou, I. Bouba, R. Kalaitzidis, I. Georgiou, M. S Elisaf, and K. C Siamopoulos Impact of renin-angiotensin-aldosterone system genes on the treatment response of patients with hypertension and metabolic syndrome Journal of Renin-Angiotensin-Aldosterone System, December 1, 2007; 8(4): 181 - 189. [Abstract] [PDF]
|
|
|
|
 |
|
 M J E van Rijn, M J Bos, A Isaacs, M Yazdanpanah, A Arias-Vasquez, B H C. Stricker, O H Klungel, B A Oostra, P J Koudstaal, J C Witteman, et al. Polymorphisms of the renin angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology J. Neurol. Neurosurg. Psychiatry, October 1, 2007; 78(10): 1083 - 1087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Martin, J. A. Buckenberger, J. Jiang, G. E. Malana, G. J. Nuovo, M. Chotani, D. S. Feldman, T. D. Schmittgen, and T. S. Elton The Human Angiotensin II Type 1 Receptor +1166 A/C Polymorphism Attenuates MicroRNA-155 Binding J. Biol. Chem., August 17, 2007; 282(33): 24262 - 24269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Iwai, K. Kajimoto, H. Tomoike, and N. Takashima Polymorphism of CYP11B2 Determines Salt Sensitivity in Japanese Hypertension, April 1, 2007; 49(4): 825 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Barr, S. M. MacKenzie, E. C. Friel, C. D. Holloway, D. M. Wilkinson, N. J.R. Brain, M. C. Ingram, R. Fraser, M. Brown, N. J. Samani, et al. Polymorphic Variation in the 11{beta}-Hydroxylase Gene Associates With Reduced 11-Hydroxylase Efficiency Hypertension, January 1, 2007; 49(1): 113 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. McNamara, S. W. Tam, M. L. Sabolinski, P. Tobelmann, K. Janosko, A. L. Taylor, J. N. Cohn, A. M. Feldman, and M. Worcel Aldosterone Synthase Promoter Polymorphism Predicts Outcome in African Americans With Heart Failure: Results From the A-HeFT Trial J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1277 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J Casal, V. J P Sinclair, A. M Capponi, J. Nicod, U. Huynh-Do, and P. Ferrari A novel mutation in the steroidogenic acute regulatory protein gene promoter leading to reduced promoter activity. J. Mol. Endocrinol., August 1, 2006; 37(1): 71 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Reyes-Engel, L. Morcillo, F. J. Aranda, M. Ruiz, M. J. Gaitan, A. Mayor-Olea, P. Aranda, and C. M. Ferrario Influence of Gender and Genetic Variability on Plasma Angiotensin Peptides Journal of Renin-Angiotensin-Aldosterone System, June 1, 2006; 7(2): 92 - 97. [Abstract] [PDF]
|
|
|
|
 |
|
 J. M C Connell and E. Davies The new biology of aldosterone J. Endocrinol., July 1, 2005; 186(1): 1 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Meneton, X. Jeunemaitre, H. E. de Wardener, and G. A. Macgregor Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases Physiol Rev, April 1, 2005; 85(2): 679 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Jacobsen Preventing end stage renal disease in diabetic patients -- genetic aspect (part I) Journal of Renin-Angiotensin-Aldosterone System, March 1, 2005; 6(1): 1 - 14. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Ganapathipillai, G. Laval, I. S. Hoffmann, A. M. Castejon, J. Nicod, B. Dick, F. J. Frey, B. M. Frey, L. X. Cubeddu, and P. Ferrari CYP11B2-CYP11B1 Haplotypes Associated with Decreased 11{beta}-Hydroxylase Activity J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1220 - 1225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kuznetsova, J. A. Staessen, L. Thijs, C. Kunath, A. Olszanecka, A. Ryabikov, V. Tikhonoff, K. Stolarz, G. Bianchi, E. Casiglia, et al. Left Ventricular Mass in Relation to Genetic Variation in Angiotensin II Receptors, Renin System Genes, and Sodium Excretion Circulation, October 26, 2004; 110(17): 2644 - 2650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Freel and J. M.C. Connell Mechanisms of Hypertension: The Expanding Role of Aldosterone J. Am. Soc. Nephrol., August 1, 2004; 15(8): 1993 - 2001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Sethi, B. G. Nordestgaard, and A. Tybjaerg-Hansen Angiotensinogen Gene Polymorphism, Plasma Angiotensinogen, and Risk of Hypertension and Ischemic Heart Disease: A Meta-Analysis Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1269 - 1275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nicod, D. Bruhin, L. Auer, B. Vogt, F. J. Frey, and P. Ferrari A Biallelic Gene Polymorphism of CYP11B2 Predicts Increased Aldosterone to Renin Ratio in Selected Hypertensive Patients J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2495 - 2500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M.C. Connell, R. Fraser, S. MacKenzie, and E. Davies Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension? Hypertension, May 1, 2003; 41(5): 993 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Cvetkovic, H. L. Keen, X. Zhang, D. Davis, B. Yang, and C. D. Sigmund Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse Physiol Genomics, December 3, 2002; 11(3): 253 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Barlassina, C. Lanzani, P. Manunta, and G. Bianchi Genetics of Essential Hypertension: From Families to Genes J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S155 - 164. [Abstract] [Full Text]
|
|
|
|
|
|
A. D. Tiago, N. J. Samani, G. P. Candy, R. Brooksbank, E. N. Libhaber, P. Sareli, A. J. Woodiwiss, and G. R. Norton Angiotensinogen Gene Promoter Region Variant Modifies Body Size-Ambulatory Blood Pressure Relations in Hypertension Circulation, September 17, 2002; 106(12): 1483 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. O. Lim, T. M. Macdonald, C. Holloway, E. Friel, N. H. Anderson, E. Dow, R. T. Jung, E. Davies, R. Fraser, and J. M. C. Connell Variation at the Aldosterone Synthase (CYP11B2) Locus Contributes to Hypertension in Subjects with a Raised Aldosterone-to-Renin Ratio J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4398 - 4402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Tiago, D. Badenhorst, D. Skudicky, A. J. Woodiwiss, G. P. Candy, R. Brooksbank, K. Sliwa, P. Sareli, and G. R. Norton An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy Cardiovasc Res, June 1, 2002; 54(3): 584 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Poch, D. Gonzalez, V. Giner, E. Bragulat, A. Coca, and A. de la Sierra Molecular Basis of Salt Sensitivity in Human Hypertension: Evaluation of Renin-Angiotensin-Aldosterone System Gene Polymorphisms Hypertension, November 1, 2001; 38(5): 1204 - 1209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ranade, K. D. Wu, N. Risch, M. Olivier, D. Pei, C.-F. Hsiao, L.-M. Chuang, L.-T. Ho, E. Jorgenson, R. Pesich, et al. Genetic variation in aldosterone synthase predicts plasma glucose levels PNAS, October 25, 2001; (2001) 221467098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Harrap and S. Petrou Utility of genetic approaches to common cardiovascular diseases Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H1 - H6. [Full Text] [PDF]
|
|
|
|
|
|
M. Azizi, M.-C. Hallouin, X. Jeunemaitre, T. T. Guyene, and J. Ménard Influence of the M235T Polymorphism of Human Angiotensinogen (AGT) on Plasma AGT and Renin Concentrations after Ethinylestradiol Administration J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4331 - 4337. [Abstract] [Full Text]
|
|
|
|
|
|
K. Ranade, K. D. Wu, N. Risch, M. Olivier, D. Pei, C.-F. Hsiao, L.-M. Chuang, L.-T. Ho, E. Jorgenson, R. Pesich, et al. Genetic variation in aldosterone synthase predicts plasma glucose levels PNAS, November 6, 2001; 98(23): 13219 - 13224. [Abstract] [Full Text] [PDF]
|
|