Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2.
BACKGROUND
Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks.


RESULTS
All 9 exons of the CYP2J2 gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism (SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at -50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects; P=0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1+/-2.4% decrease in CYP2J2 promoter activity (P<0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP.


CONCLUSIONS
A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary artery disease.
Department of Medicine II/Cardiology, St. Josef-Hospital, University of Bochum, Gudrunstr 56, 44791 Bochum, Germany. martin.spiecker@ruhr-uni-bochum.de
Martin
M
Spiecker
Harald
H
Darius
Thomas
T
Hankeln
Muhidien
M
Soufi
Alexander M
AM
Sattler
Jürgen R
JR
Schaefer
Koichi
K
Node
Jan
J
Börgel
Andreas
A
Mügge
Klaus
K
Lindpaintner
Anika
A
Huesing
Bernhard
B
Maisch
Darryl C
DC
Zeldin
James K
JK
Liao
D020413:3' Untranslated Regions / Q000235:genetics; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives; D000368:Aged; D019943:Amino Acid Substitution; D016718:Arachidonic Acid / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D015777:Eicosanoids / Q000096:biosynthesis; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012306:Risk; D017422:Sequence Analysis, DNA; D016329:Sp1 Transcription Factor / Q000378:metabolism
C107016:14,15-dihydroxyeicosatrienoic acid; D020413:3' Untranslated Regions; C000717350:CYP2J2 protein, human; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D016329:Sp1 Transcription Factor; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid