β1-和α2C-肾上腺素能受体的协同多态性与充血性心力衰竭风险

Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure.

作者信息

Small Kersten M, Wagoner Lynne E, Levin Albert M, Kardia Sharon L R, Liggett Stephen B

机构信息

Division of Pulmonary Medicine, University of Cincinnati College of Medicine, Cincinnati 45267-0564, USA.

出版信息

N Engl J Med. 2002 Oct 10;347(15):1135-42. doi: 10.1056/NEJMoa020803.

DOI:10.1056/NEJMoa020803

PMID:12374873

Abstract

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 alpha2-adrenergic receptors, and the targets of the released norepinephrine on myocytes are beta1-adrenergic receptors. In transfected cells, a polymorphic alpha2C-adrenergic receptor (alpha2CDel322-325) has decreased function, and a variant of the beta1-adrenergic receptor (beta1Arg389) 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 alpha2CDel322-325 as compared with those with the other alpha2C-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 beta1Arg389 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 alpha2CDel322-325 and beta1Arg389 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.

摘要

背景

心脏肾上腺素能的持续刺激与心力衰竭的发生和发展有关。去甲肾上腺素的释放受突触前α2 - 肾上腺素能受体负反馈的控制，释放的去甲肾上腺素作用于心肌细胞上的靶点是β1 - 肾上腺素能受体。在转染细胞中，一种多态性α2C - 肾上腺素能受体（α2CDel322 - 325）功能降低，而β1 - 肾上腺素能受体的一种变体（β1Arg389）功能增强。我们推测，这种受体变体的组合会导致突触去甲肾上腺素释放增加以及心肌细胞上受体功能增强，从而使个体易患心力衰竭。

方法

对159例心力衰竭患者和189例对照者进行这些位点的基因分型。采用逻辑回归方法确定每种基因型及其之间的相互作用对心力衰竭风险的潜在影响。

结果

在黑人受试者中，与其他α2C - 肾上腺素能受体基因型的个体相比，α2CDel322 - 325纯合子个体发生心力衰竭的校正比值比为5.65（95%置信区间为2.67至11.95；P<0.001）。单独的β1Arg389不会增加风险。然而，两种变体均为纯合子的个体发生心力衰竭的风险显著增加（校正比值比为10.11；95%置信区间为2.11至48.53；P = 0.004）。心力衰竭患者与对照者在9个短串联重复等位基因的频率上没有差异。在白人受试者中，两种多态性均为纯合子的个体太少，无法充分评估风险。