Copyright © 2000 by the European Society of Cardiology.
A novel polymorphism in the gene coding for the beta1-adrenergic receptor associated with survival in patients with heart failure
Wallenberg Laboratory for Cardiovascular Research, Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden
revised October 19, 1999; accepted October 20, 1999
Abstract
Aims The adrenergic nervous system is of major importance in congestive heart failure. No genetic polymorphism has previously been identified in the beta1-adrenergic receptor gene. The aim of this study was to find possible mutations in this gene and to relate such findings to morbidity and prognosis in heart failure.
Methods and Results Genomic DNA was extracted from blood leukocytes from patients with congestive heart failure (n=184) and from age-matched controls (n=77). The part of the beta1-adrenergic receptor gene corresponding to nucleotide 1–255 was amplified by polymerase chain reaction and analysed by automated sequencing. The patients were investigated by echocardiography and followed regarding symptoms and survival for 5 years. A missense mutation was identified at nucleotide position 145 in the beta1-adrenergic receptor gene, which predicted an amino acid substitution at position 49 (Ser49Gly). The allele frequency of the Gly49 variant was 0·13 in controls and 0·18 in patients (P=0·19). At the time of the 5-years follow-up, 62% of the patients with the wild type gene and 39% of the patients with the Ser49Gly variant had died or had experienced hospitalization (P=0·005). Patients without the mutation had significantly poorer survival compared to those with the mutation, risk ratio 2·34 (95% CI 1·30–4·20), P=0·003. In a mulivariate analysis, the risk ratio was 2·03 (95% CI 0·99–4·16)P =0·05.
Conclusion A novel missense mution in the beta1-adrenergic receptor gene was associated with a decreased mortality risk in patients with congestive heart failure. These data suggest that the beta1-receptor Ser49Gly variant might be associated with altered receptor function, resulting in myocardial protection in patients with heart failure.
Key Words: Polymorphism (genetics), receptors, adrenergic, beta1, prognosis, congestive heart failure, congestive cardiomyopathy, hospitalization
f1 Correspondence: Dr Bert Andersson, Dept of Cardiology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.
References
- Waagstein F, Hjalmarson
, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J. 1975;37:1022–1036[Abstract/Free Full Text] - Lancet. 1998;351:1180–1181[ISI][Medline]
- Lancet. 1999;353:9–13[CrossRef][ISI][Medline]
- Lancet. 1999;353:2001–2007[CrossRef][ISI][Medline]
- Liggett SB. Genetics of beta 2-adrenergic receptor variants in asthma. Clin Exp Allergy. 1995;25:89–94[ISI][Medline]
- Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest. 1995;95:1635–1641[ISI][Medline]
- Large V, Hellstrom L, Reynisdottir S. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest. 1997;100:3005–3013[ISI][Medline]
- Liggett SB, Wagoner LE, Craft LL. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest. 1998;102:1534–1539[ISI][Medline]
- Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Koblika BK. Cloning of the cDNA for the human ß1-adrenergic receptor. Proc Natl Acad Sci USA. 1987;84:7920–7924
[Abstract/Free Full Text] - Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG. Chromosomal organization of adrenergic receptor genes. Proc Natl Acad Sci USA. 1990;87:1516–1520
[Abstract/Free Full Text] - Börjesson M, Magnusson Y, Andersson B. A novel polymorphism in the gene coding for the ß1-receptor associated with survival in patients with heart failure (Abstr). J Am Coll Cardiol. 1999;33:261A
- Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem. 1999;274:12670–12674
[Abstract/Free Full Text] - Tesson F, Charron P, Peuchmaurd M. Characterization of a unique genetic variant in the beta1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. J Mol Cell Cardiol. 1999;31:1025–1032[CrossRef][ISI][Medline]
- Andersson B, Waagstein F. Spectrum and outcome of congestive heart failure in a hospitalized population. Am Heart J. 1993;126:632–640[CrossRef][ISI][Medline]
- Andersson B, Caidahl K, Waagstein F. Idiopathic dilated cardiomyopathy among Swedish patients with congestive heart failure. Eur Heart J. 1995;16:53–60[Medline]
- Andersson B, Caidahl K, Waagstein F. An echocardiographic evaluation of patients with idiopathic heart failure. Chest. 1995;107:680–689[CrossRef][Medline]
- Dixon RA, Sigal IS, Candelore MR, Register RB. Structural features required for ligand binding to the beta-adrenergic receptor. EMBO J. 1987;6:3269–3275[ISI][Medline]
- Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33:9414–9419[CrossRef][Medline]
- Bristow MR, Ginsburg R, Minobe W. Decreased catecholamine sensitivity and ß-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205–211[Abstract]
- Magnusson Y, Marullo S, Höyer S. Mapping of a functional autoimmune epitope on the ß1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J Clin Invest. 1990;86:1658–1663[ISI][Medline]
- Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, Hoebeke J. Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta1adrenoceptor with positive chronotropic effect. Circulation. 1994;89:2760–2767
[Abstract/Free Full Text] - Böhm M, Gierschik P, Jakobs K-H. Increase of Gi-alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation. 1990;82:1249–1265
[Abstract/Free Full Text] - Bristow MR, Anderson FL, Port JD. Differences in ß-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation. 1991;84:1024–1039
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Hassan, K. M. York, H. Li, Q. Li, Y. Gong, T. Y. Langaee, R. B. Fillingim, J. A. Johnson, and D. S. Sheps Association of {beta}1-Adrenergic Receptor Genetic Polymorphism With Mental Stress-Induced Myocardial Ischemia in Patients With Coronary Artery Disease Arch Intern Med, April 14, 2008; 168(7): 763 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Richard, E. Villard, P. Charron, and R. Isnard The Genetic Bases of Cardiomyopathies J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A79 - A89. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Zaroff, L. Pawlikowska, J. C. Miss, S. Yarlagadda, C. Ha, A. Achrol, P.-Y. Kwok, C. E. McCulloch, M. T. Lawton, N. Ko, et al. Adrenoceptor Polymorphisms and the Risk of Cardiac Injury and Dysfunction After Subarachnoid Hemorrhage Stroke, July 1, 2006; 37(7): 1680 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nieminen, T. Lehtimaki, J. Laiho, R. Rontu, K. Niemela, T. Koobi, R. Lehtinen, J. Viik, V. Turjanmaa, and M. Kahonen Effects of polymorphisms in beta1-adrenoceptor and {alpha}-subunit of G protein on heart rate and blood pressure during exercise test. The Finnish Cardiovascular Study J Appl Physiol, February 1, 2006; 100(2): 507 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wojnowski, B. Kulle, M. Schirmer, G. Schluter, A. Schmidt, A. Rosenberger, S. Vonhof, H. Bickeboller, M. R. Toliat, E.-K. Suk, et al. NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity Circulation, December 13, 2005; 112(24): 3754 - 3762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kaye, B. Smirk, S. Finch, C. Williams, and M. D. Esler Interaction between cardiac sympathetic drive and heart rate in heart failure: Modulation by adrenergic receptor genotype J. Am. Coll. Cardiol., November 16, 2004; 44(10): 2008 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Covolo, U. Gelatti, M. Metra, S. Nodari, A. Piccichè, N. Pezzali, C. Zani, A. Alberti, F. Donato, G. Nardi, et al. Role of {beta}1- and {beta}2-adrenoceptor polymorphisms in heart failure: a case-control study Eur. Heart J., September 1, 2004; 25(17): 1534 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fehr, D. R. Zimmermann, R. P. Wuthrich, and P. Ammann A young renal transplant recipient with unexplained resting sinus tachycardia, hypertension and {beta}-blocker resistance Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1646 - 1649. [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kirstein and P. A. Insel Autonomic Nervous System Pharmacogenomics: A Progress Report Pharmacol. Rev., March 1, 2004; 56(1): 31 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Le Corvoisier, H.-Y. Park, K. M. Carlson, D. A. Marchuk, and H. A. Rockman Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy Hum. Mol. Genet., December 1, 2003; 12(23): 3097 - 3107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Meisel, K. Kopke, I. Roots, M. L. Maitland, M. Gomberg-Maitland, J. Little, M. Gwinn, M. Khoury, S. L.R. Kardia, A. M. Levin, et al. Polymorphisms of Adrenergic Receptors and the Risk of Heart Failure N. Engl. J. Med., January 30, 2003; 348(5): 468 - 470. [Full Text] [PDF]
|
|
|
|
|
|
P. Molenaar, G. Rabnott, I. Yang, K. M. Fong, S. M. Savarimuthu, L. Li, M. J. West, and F. D. Russell Conservation of the cardiostimulant effects of (-)-norepinephrine across Ser49Gly and Gly389Arg beta1-adrenergic receptor polymorphisms in human right atrium in vitro J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1275 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Levin, S. Marullo, O. Muntaner, B. Andersson, and Y. Magnusson The Myocardium-protective Gly-49 Variant of the beta 1-Adrenergic Receptor Exhibits Constitutive Activity and Increased Desensitization and Down-regulation J. Biol. Chem., August 16, 2002; 277(34): 30429 - 30435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.L. White, A. Maqbool, A.D. McMahon, L. Yates, S.G. Ball, A.S. Hall, and A.J. Balmforth An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals at risk of coronary events. A WOSCOPS substudy Eur. Heart J., July 2, 2002; 23(14): 1087 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.G. Mahon and W.J. Mckenna Genes and acquired disease: beta-adrenoceptor polymorphisms and heart failure Eur. Heart J., November 2, 2000; 21(22): 1810 - 1812. [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||