CYP4A11 polymorphism correlates with coronary endothelial dysfunction in patients with coronary artery disease--the ENCORE Trials.
BACKGROUND
Cytochrome P450 (CYP) is expressed in the human endothelium and metabolizes arachidonic acid into vasoactive epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids. CYP enzymes have been linked to hypertension and generation of reactive oxygen species. Thus, we investigated the impact of several CYP polymorphisms on coronary endothelial function in patients with coronary artery disease (CAD).


RESULTS
We determined CYP4A11 F434S, CYP2C9 I359L, CYP2C9 G144C and CYP 2J2 promotor -50G>T polymorphisms in 734 patients with CAD undergoing percutaneous coronary intervention. Increasing concentrations of acetylcholine were infused in a coronary segment without angiographically significant CAD and the coronary artery vasomotor response was measured by quantitative angiography. Patients with substitution of phenylalanine 434 by serine (434SS, n=15, 2.04%) in CYP4A11 F434 demonstrated significantly augmented endothelium-dependent vasoconstriction (p=0.044 after Bonferroni correction) compared to patients with the 434FS (n=193, 26.29%) and 434FF genotype (n=526, 71.66%) before and after adjustment for blood pressure and HDL-cholesterol. In addition, patients with the 434SS genotype had higher systolic blood pressure levels (p=0.039) compared to the two other groups. The CYP 2C9 and CYP 2J2 polymorphisms did not show any correlation with coronary vasoconstriction, hypertension, diabetes mellitus, blood pressure or cholesterol.


CONCLUSIONS
In patients with established and stable coronary artery disease the 434SS variant of CYP4A11 F434 is associated with pronounced coronary vasoconstriction.
Hermann
M
M
Klinik für Kardiologie, Universitätsspital, Zürich, Switzerland.
Hellermann
J P
JP
Quitzau
K
K
Hoffmann
M M
MM
Gasser
T
T
Meinertz
T
T
Münzel
T
T
Fleming
I
I
Lüscher
T F
TF
D000109:Acetylcholine / Q000008:administration & dosage; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000235:genetics; D002986:Clinical Trials as Topic; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D003404:Creatinine / Q000097:blood; D065729:Cytochrome P-450 CYP2C9; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics*
D015415:Biomarkers; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000090762:Cytochrome P-450 CYP2J2; C465478:CYP4A11 protein, human; D042926:Cytochrome P-450 CYP4A; D000109:Acetylcholine