Risk of coronary artery disease as influenced by variants of the human endothelin and endothelin-converting enzyme genes.
OBJECTIVE
The potent vasoconstrictor endothelin (ET) is generated by enzymatic cleavage catalyzed by the endothelin-converting enzyme 1 (ECE-1) and plays a crucial role in the regulation of vascular tone and endothelial function. Polymorphisms of the ET and ECE genes may contribute to the development and progression of coronary artery disease. Recently, we have shown the functional relevance of the +138 adenine ins/del polymorphism on ET-1 expression in vitro. The aim of our case-control study was to investigate the impact of known and novel variants of the ET and ECE genes on the risk of coronary artery disease in vivo.


METHODS
In a prestudy, 36 single nucleotide polymorphisms in the ET-1, ET-2, ET-3 and ECE-1 genes were identified in 55 participants by sequencing analysis. Subsequently, 1000 matched pairs of angiographically confirmed coronary artery disease patients and hospital controls were genotyped for the eight most common or functionally relevant variants of the ET-1 (138 A ins/del, 2176T>G, 3660G>A, 5665G>T (Lys198Asn)) and ECE-1 gene (-854C>T, -839T>G, -377G>A, and exon 9 +2C>T).


RESULTS
Carriers of at least one copy of the dysfunctional ET-1 5665 T allele were at increased risk of coronary artery disease (odds ratio 1.25; 95% confidence interval 1.03-1.52, P=0.025), particularly among men (odds ratio 1.32; 95% confidence interval 1.06-1.65, P=0.014). Homozygous carriers of the ECE-1 -839G variant allele exhibited a decreased risk of coronary artery disease (odds ratio 0.41; 95% confidence interval 0.18-0.90, P=0.024). The other six screened variants showed no association with coronary artery disease, the overall haplotype distribution differed slightly but significantly.


CONCLUSIONS
This large case-control study argues for an only minor-if any-role of the ET-1 and ECE-1 genotype for the risk of coronary artery disease development.
Bühler
Katrin
K
Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
Ufer
Mike
M
Müller-Marbach
Alexis
A
Brinkmann
Ulrich
U
Laule
Michael
M
Stangl
Verena
V
Roots
Ivar
I
Stangl
Karl
K
Cascorbi
Ingolf
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D016232:Endothelins; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes