November 27, 2002 Access past issues

Reviewed by: Julian Little Office of Genomics and Disease Prevention, CDC Epidemiology Group, Department of Medicine & Therapeutics, Aberdeen University, Aberdeen, UK

The Health Outcome

Congestive heart failure is a sequel to various heart diseases and is often the end stage of cardiac disease. Half of the patients diagnosed with congestive heart failure will die within 5 years, and one in five persons dies within 1 year (1) . In the United States, an estimated 4.8 million people have the condition, and each year, 400,000 new cases are diagnosed (2) . The incidence does not vary by sex, but it increases with age, with an annual incidence approaching 10 per 1000 after 65 years of age. The prevalence increased substantially during 1976-1991 and is expected to increase because a) as more patients with heart diseases survive with their disease, their opportunity for developing congestive heart failure increases, and b) the elderly population is expected to increase. The National Heart, Lung, and Blood Institute has described the increase in congestive heart failure as a “new epidemic” (1) . The prevalence is at least 25 percent greater among the black population than among the white population. During 1971-2000, hospitalization rates attributed to the condition more than tripled for persons aged 45-64 years and 65 years and older. The annual expenditure for health and lost productivity from the condition is estimated to be $23.2 billion (2) .

Variation in penetrance of familial cardiomyopathy and strain-specific effects in animal models suggest a role for genetic factors in the etiology of congestive heart failure (3) . Associations have been investigated between congestive heart failure and genetic polymorphisms postulated to influence susceptibility, such as the angiotensin-converting enzyme gene, the angiotensin type I receptor gene, the endothelin-A receptor gene, and the beta 1-adrenergic receptor gene.

The Finding

Small et al. (4) reported that variants of the α_2cDel322-325 and β₁Arg389 receptor genes interacted to increase the risk for congestive heart failure. This finding was made in a case-control study in the greater Cincinnati area that comprised 159 persons with either idiopathic dilated or ischemic cardiomyopathy and 189 controls who were blood donors or had responded to newspaper advertisements (further details of methods and critique are presented in the accompanying abstraction template). All of these persons were genotyped to determine the presence of the Del322-325 variant of the alpha 2C-adrenergic receptor gene (ADRA2C), and the Arg389 (1165G>C) variant of the beta 1- adrenergic receptor gene (ADRB1). No association with ADRB1 genotype was apparent. Homozygosity for the α_2cDel322-325 variant was associated with a 4.5-fold increase in the risk for congestive heart failure. In subgroup analysis by ethnic group, evidence of a supramultiplicative interaction between the variants was apparent in black persons but not in white persons. Therefore, the authors concluded that α_2cDel322-325 and β₁Arg389 receptor variants act synergistically to increase the risk for heart failure in blacks. They suggested that genotyping at these two loci may be a useful for identifying persons at risk for heart failure or its progression who may be candidates for early preventive measures.

Public Health Implications

Although this finding is intriguing, selection bias and low statistical power may have influenced the validity of the results (see accompanying abstract for detailed comment).

The finding with ADRA2C is novel. On the basis of studies of mice in which the gene for the alpha-2c adrenergic receptor has been inactivated (4) , and the observation that the heart is one of the organs in which expression of this receptor predominates relative to other subtypes (5) , the association is biologically plausible.

ADRB1 has been investigated in relation to a number of cardiovascular outcomes. In single studies, no association with resting heart rate (6) , acquired long QT syndrome (7) or coronary events (nonfatal myocardial infarction, death from coronary artery disease, or disease that led to revascularisation procedure) (8) has been observed. No association with heart rate response to exercise was observed in two small studies (9, 10) . In two studies, no association with dilated cardiomyopathy was observed (11, 12) , In the Japanese study of dilated cardiomyopathy, Gly389 suppressed the occurrence of ventricular tachycardia, suggesting that this allele confers a decreased risk of sudden death (12) . Associations with blood pressure and hypertension have been inconsistent (6, 13, 14) . Thus, the results relating to cardiovascular outcomes are inconsistent.

In two studies of the relation of this polymorphism with determinants of obesity that differed markedly in design and setting, apparently conflicting results were obtained (15, 16) .

In view of the novelty of the finding in relation to one of the variants, and the lack of consistency of association for the other, the implications of the study of Small et al. (4) for the prevention of congestive heart failure are uncertain. Large population-based studies of these associations are needed.

References

1. National Heart, Lung, and Blood Institute. Data fact sheet. Congestive heart failure in the United States: A new epidemic. 1996. Bethesda, MD: U.S. Department of Health and Human Services.
2. National Heart, Lung, and Blood Institute. Morbidity & mortality: 2002 chart book on cardiovascular, lung, and blood diseases. 2002. Bethesda, MD: U.S. Department of Health and Human Services.
3. Hajjar RJ, MacRae CA. Adrenergic-receptor polymorphisms and heart failure. N Engl J Med 2002;347:1196-9.
4. Small KM, Wagoner LE, Levin AM, et al. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 2002;347:1135-42.
5. Feng J, Zheng J, Gelernter J, et al. An in-frame deletion in the alpha(2C) adrenergic receptor is common in African-Americans. Mol Psychiatry 2001;6:168-72.
6. Ranade K, Jorgenson E, Sheu WH, et al. A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet 2002;70:935-42.
7. Kanki H, Yang P, Xie HG, et al. Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. J Cardiovasc Electrophysiol 2002;13:252-6.
8. White HL, Maqbool A, McMahon AD, et al. An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals at risk of coronary events. A WOSCOPS substudy. Eur Heart J 2002;23:1087-92.
9. Buscher R, Belger H, Eilmes KJ, et al. In-vivo studies do not support a major functional role for the Gly389Arg beta 1-adrenoceptor polymorphism in humans. Pharmacogenetics 2001;11:199-205.
10. Xie HG, Dishy V, Sofowora G, et al. Arg389Gly beta 1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo. Pharmacogenetics 2001;11:191-7.
11. Tesson F, Charron P, Peuchmaurd M, et al. Characterization of a unique genetic variant in the beta1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group. J Mol Cell Cardiol 1999;31:1025-32.
12. Iwai C, Akita H, Shiga N, et al. Suppressive effect of the Gly389 allele of the beta1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy. Circ J 2002;66:723-8.
13. Bengtsson K, Melander O, Orho-Melander M, et al. Polymorphism in the beta(1)-adrenergic receptor gene and hypertension. Circulation 2001;104:187-90.
14. McCaffery JM, Pogue-Geile MF, Ferrell RE, et al. Variability within alpha- and beta-adrenoreceptor genes as a predictor of cardiovascular function at rest and in response to mental challenge. J Hypertens 2002;20:1105-14.
15. Ryden M, Hoffstedt J, Eriksson P, et al. The Arg 389 Gly beta1-adrenergic receptor gene polymorphism and human fat cell lipolysis. Int J Obes Relat Metab Disord 2001;25:1599-603.
16. Dionne IJ, Garant MJ, Nolan AA, et al. Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women. Int J Obes Relat Metab Disord 2002;26:633-9.