Published online before print August 18, 2003, doi: 10.1161/01.HYP.0000088853.27673.D0
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2003;42:500.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension
From the Centre for Cardiovascular Genetics, Royal Free and University College Medical School, London, UK, and Medical Research Council Cardiovascular Research Group (G.J.M.), Wolfson Institute of Preventative Medicine, London, UK.
Correspondence to Dr Hugh E. Montgomery, Portex Senior Lecturer in Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College Medical School, Rayne Building, 5 University Street, London WC1E 6JF, UK. E-mail h.montgomery{at}ucl.ac.uk
Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT1R) and (potentially antiatherogenic) inducible type 2 (AT2R) receptors. We explored such potential roles in a prospective candidate gene association study. Cardiovascular end points (fatal, nonfatal, and silent myocardial infarction and coronary artery bypass surgery/angioplasty) were documented among 2579 healthy UK men (mean age, 56.1±3.5 years; median follow-up, 10.1 years) genotyped for the AT1R1166A>C and the X chromosome located AT2R1675A>G and 3123C>A polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT1R1166CC genotype was associated with relative cardiovascular risk (hazard ratio, 1.65 [1.05 to 2.59]; P=0.03) independent of blood pressure. Systolic blood pressure was associated with risk (P=0.0005), but this association was restricted to AT2R1675A allele carriers (P<0.00001), with G allele carriers protected from the risk associated with blood pressure (P=0.18). Hypertensive carriers with the AT2R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT2R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT2R is protective. Conversely, the AT1R1166CC genotype was associated with cardiovascular risk irrespective of blood pressure. These data are important to our understanding of the divergent role of angiotensin II acting at its receptor subtypes and coronary disease pathogenesis and for the development of future cardiovascular therapies.
Key Words: receptors, angiotensin II • genetics • polymorphism • cardiovascular diseases • hypertension, genetic
This article has been cited by other articles:
 |
|
 |
|
  Bhoomi Reddy Pullareddy, Baddela Muni Venkata Srikanth Babu, Kolla Venkata Karunakar, J. Yasovanthi, Potham Sampath Kumar, A. Sharath, and A. Jyothy Angiotensin II type 1 receptor gene polymorphism in myocardial infarction patients Journal of Renin-Angiotensin-Aldosterone System, September 1, 2009; 10(3): 174 - 178. [Abstract] [PDF]
|
|
|
|
 |
|
 O. A. Iakoubova, C. H. Tong, C. M. Rowland, T. G. Kirchgessner, B. A. Young, A. R. Arellano, D. Shiffman, M. S. Sabatine, H. Campos, C. J. Packard, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 435 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Marciante, J. C. Bis, M. J. Rieder, A. P. Reiner, T. Lumley, S. A. Monks, C. Kooperberg, C. Carlson, S. R. Heckbert, and B. M. Psaty Renin-Angiotensin System Haplotypes and the Risk of Myocardial Infarction and Stroke in Pharmacologically Treated Hypertensive Patients Am. J. Epidemiol., July 1, 2007; 166(1): 19 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Ntzani, E. C. Rizos, and J. P. A. Ioannidis Genetic Effects versus Bias for Candidate Polymorphisms in Myocardial Infarction: Case Study and Overview of Large-Scale Evidence Am. J. Epidemiol., May 1, 2007; 165(9): 973 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Su, L. Lee, X. Li, J. Lv, Y. Hu, S. Zhan, W. Cao, L. Mei, Y.-M. Tang, D. Wang, et al. Association Between Angiotensinogen, Angiotensin II Receptor Genes, and Blood Pressure Response to an Angiotensin-Converting Enzyme Inhibitor Circulation, February 13, 2007; 115(6): 725 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Humphries, J. A. Cooper, P. J. Talmud, and G. J. Miller Candidate Gene Genotypes, Along with Conventional Risk Factor Assessment, Improve Estimation of Coronary Heart Disease Risk in Healthy UK Men Clin. Chem., January 1, 2007; 53(1): 8 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nishikino, T. Matsunaga, K. Yasuda, T. Adachi, T. Moritani, G. Tsujimoto, K. Tsuda, and N. Aoki Genetic Variation in the Renin-Angiotensin System and Autonomic Nervous System Function in Young Healthy Japanese Subjects J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4676 - 4681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Warnecke, P. Mugrauer, D. Surder, J. Erdmann, C. Schubert, and V. Regitz-Zagrosek Intronic ANG II type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1729 - R1735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Carey Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor: The AT2 Receptor Comes of Age Hypertension, May 1, 2005; 45(5): 840 - 844. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Alfakih, R. A. Lawrance, A. Maqbool, K. Walters, S. G. Ball, A. J. Balmforth, and A. S. Hall The clinical significance of a common, functional, X-linked angiotensin II type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease Eur. Heart J., March 2, 2005; 26(6): 584 - 589. [Abstract] [Full Text] [PDF]
|
|