[HTML][HTML] Synergistic Polymorphisms of β1- and α2C-Adrenergic Receptors and the Risk of Congestive Heart Failure

KM Small, LE Wagoner, AM Levin… - … England Journal of …, 2002 - Mass Medical Soc
KM Small, LE Wagoner, AM Levin, SLR Kardia, SB Liggett
New England Journal of Medicine, 2002Mass Medical Soc
Background Sustained cardiac adrenergic stimulation has been implicated in the
development and progression of heart failure. Release of norepinephrine is controlled by
negative feedback from presynaptic α2-adrenergic receptors, and the targets of the released
norepinephrine on myocytes are β1-adrenergic receptors. In transfected cells, a polymorphic
α2C-adrenergic receptor (α2CDel322–325) has decreased function, and a variant of the β1-
adrenergic receptor (β1Arg389) has increased function. We hypothesized that this …
Background
Sustained cardiac adrenergic stimulation has been implicated in the development and progression of heart failure. Release of norepinephrine is controlled by negative feedback from presynaptic α2-adrenergic receptors, and the targets of the released norepinephrine on myocytes are β1-adrenergic receptors. In transfected cells, a polymorphic α2C-adrenergic receptor (α2CDel322–325) has decreased function, and a variant of the β1-adrenergic receptor (β1Arg389) has increased function. We hypothesized that this combination of receptor variants, which results in increased synaptic norepinephrine release and enhanced receptor function at the myocyte, would predispose persons to heart failure.
Methods
Genotyping at these loci was performed in 159 patients with heart failure and 189 controls. Logistic-regression methods were used to determine the potential effect of each genotype and the interaction between them on the risk of heart failure.
Results
Among black subjects, the adjusted odds ratio for heart failure among persons who were homozygous for α2CDel322–325 as compared with those with the other α2C-adrenergic receptor genotypes was 5.65 (95 percent confidence interval, 2.67 to 11.95; P<0.001). There was no increase in risk with β1Arg389 alone. However, there was a marked increase in the risk of heart failure among persons who were homozygous for both variants (adjusted odds ratio, 10.11; 95 percent confidence interval, 2.11 to 48.53; P=0.004). The patients with heart failure did not differ from the controls in the frequencies of nine short tandem-repeat alleles. Among white subjects, there were too few who were homozygous for both polymorphisms to allow an adequate assessment of risk.
Conclusions
The α2CDel322–325 and β1Arg389 receptors act synergistically to increase the risk of heart failure in blacks. Genotyping at these two loci may be a useful approach for identification of persons at risk for heart failure or its progression, who may be candidates for early preventive measures.
The New England Journal Of Medicine