ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms in heart failure. A case-control study.
BACKGROUND
The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ET(A) (T/C in exon 6, H323H) could predispose carriers to heart failure (HF).


METHODS
Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) < or =40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26).


RESULTS
The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ET(A) variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ET(A )polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = -0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = -0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis.


CONCLUSIONS
The ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.
CNR Institute of Clinical Physiology, Massa, Italy. Colombo@ifc.cnr.it
Maria Giovanna
MG
Colombo
Enrica
E
Ciofini
Umberto
U
Paradossi
Stefano
S
Bevilacqua
Andrea
A
Biagini
D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003062:Codon; D017023:Coronary Angiography; D004452:Echocardiography; D019332:Endothelin-1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044022:Receptor, Endothelin A / Q000235:genetics*; D012044:Regression Analysis; D012307:Risk Factors
D003062:Codon; D019332:Endothelin-1; D044022:Receptor, Endothelin A