A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Herrmann
S
S
Institute of Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology, Benjamin Franklin Medical Center, Freie Universität Berlin, Germany.
Schmidt-Petersen
K
K
Pfeifer
J
J
Perrot
A
A
Bit-Avragim
N
N
Eichhorn
C
C
Dietz
R
R
Kreutz
R
R
Paul
M
M
Osterziel
K J
KJ
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D000483:Alleles; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D017023:Coronary Angiography; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects; D012720:Severity of Illness Index; D013318:Stroke Volume / Q000502:physiology; D016019:Survival Analysis; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin