Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2

• Published in: Circulation (New York, N.Y.) N.Y.), 2004-10, Vol.110 (15), p.2132-2136
• Main Authors: SPIECKER, Martin, DARIUS, Harald, HUESING, Anika, MAISCH, Bernhard, ZELDIN, Darryl C, LIAO, James K, HANKELN, Thomas, SOUFI, Muhidien, SATTLER, Alexander M, SCHAEFER, Jürgen R, NODE, Koichi, BÖRGEL, Jan, MÜGGE, Andreas, LINDPAINTNER, Klaus
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; 8,11,14-Eicosatrienoic Acid - analogs & derivatives; Aged; Amino Acid Substitution; Arachidonic Acid - metabolism; Atherosclerosis (general aspects, experimental research); Base Sequence; Binding Sites - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary Disease - epidemiology; Coronary Disease - genetics; Coronary heart disease; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - physiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA Mutational Analysis; Eicosanoids - biosynthesis; Exons - genetics; Female; Genetic Testing; Genotype; Germany - epidemiology; Heart; Humans; Hydroxyeicosatetraenoic Acids - blood; Introns - genetics; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Oxygenases - genetics; Oxygenases - physiology; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Risk; Sequence Analysis, DNA; Sp1 Transcription Factor - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000143832.91812.60

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. 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