Herrmann S, Schmidt-Petersen K, Pfeifer J, Perrot A, Bit-Avragim N, Eichhorn C, Dietz R, Kreutz R, Paul M, Osterziel K J
Institute of Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology, Benjamin Franklin Medical Center, Freie Universität Berlin, Germany.
Eur Heart J. 2001 Oct;22(20):1948-53. doi: 10.1053/euhj.2001.2626.
The endothelin system plays a role in the complex pathophysiology of idiopathic dilated cardiomyopathy. We investigated whether genetic polymorphisms of the endothelin system might be associated with dilated cardiomyopathy-related cardiac phenotypes and differences in disease outcome.
One hundred and twenty-five unrelated dilated cardiomyopathy patients of a well characterized dilated cardiomyopathy cohort were genotyped for six common polymorphisms of the endothelin-1, endothelin-A (ETA) and endothelin-B (ETB) receptor genes using hybridization with allele-specific oligonucleotides.
The H323H (C/T) polymorphism in exon 6 of the ETA receptor gene was significantly associated with a shorter survival time after diagnosis. The odds ratio for carriers of the less frequent ET(A)T allele to die within 2 years after diagnosis was 5.5 (95% confidence interval, 1.4 to 21.0, P=0.013) compared to non-carriers. Kaplan-Meier analysis revealed a significantly different survival time for T allele carriers as compared to non-carriers as tested by logrank (P=0.0196), Breslow (P=0.0195), and Tarone tests (P=0.020). The influence of the ETA H323H polymorphism on survival remained significant when known predictors of prognosis such as left ventricular ejection fraction, left ventricular end-diastolic diameter, age and NYHA functional classification were entered in a Cox proportional hazards analysis. In this model, end-diastolic diameter showed a trend to influence survival (P=0.07) but only the ETA H323H polymorphism (P=0.0029) was a significant independent predictor of survival.
Our results suggest that genetic variation in the ETA receptor predicts survival in dilated cardiomyopathy patients, which might have important consequences for the identification of high-risk individuals.
内皮素系统在特发性扩张型心肌病复杂的病理生理学中发挥作用。我们研究了内皮素系统的基因多态性是否可能与扩张型心肌病相关的心脏表型及疾病预后差异有关。
使用等位基因特异性寡核苷酸杂交技术，对一个特征明确的扩张型心肌病队列中的125例无亲缘关系的扩张型心肌病患者进行内皮素-1、内皮素-A（ETA）和内皮素-B（ETB）受体基因的6种常见多态性基因分型。
ETA受体基因第6外显子中的H323H（C/T）多态性与诊断后的生存时间缩短显著相关。与非携带者相比，诊断后2年内死亡的低频ET(A)T等位基因携带者的比值比为5.5（95%置信区间，1.4至21.0，P = 0.013）。Kaplan-Meier分析显示，通过对数秩检验（P = 0.0196）、Breslow检验（P = 0.0195）和Tarone检验（P = 0.020），T等位基因携带者与非携带者的生存时间有显著差异。当在Cox比例风险分析中纳入左心室射血分数、左心室舒张末期直径、年龄和纽约心脏协会功能分级等已知预后预测因素时，ETA H323H多态性对生存的影响仍然显著。在该模型中，舒张末期直径显示出影响生存的趋势（P = 0.07），但只有ETA H323H多态性（P = 0.0029）是生存的显著独立预测因素。
我们的数据表明，ETA受体的基因变异可预测扩张型心肌病患者的生存情况，这可能对识别高危个体具有重要意义。
