Published Online
on October 4, 2004

A more recent version of this article appeared on October 12, 2004

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Submitted on January 28, 2004
Revised on May 12, 2004
Accepted on May 19, 2004

Risk of Coronary Artery Disease Associated With Polymorphism of the Cytochrome P450 Epoxygenase CYP2J2

Martin Spiecker MD, Harald Darius MD^*, Thomas Hankeln PhD, Muhidien Soufi PhD, Alexander M. Sattler MD, Jürgen R. Schaefer MD, Koichi Node MD, Jan Börgel MD, Andreas Mügge MD, Klaus Lindpaintner MD, Anika Huesing MSc, Bernhard Maisch MD, Darryl C. Zeldin MD, and James K. Liao MD

From the Department of Medicine II (M. Spiecker, J.B., A.M.), St. Josef-Hospital, and Department of Medical Statistics (A.H.), University of Bochum, Bochum, Germany; Department of Medicine II (H.D.), University of Mainz, Mainz, Germany; GENterprise GmbH (T.H.), Mainz, Germany; Department of Medicine (M. Soufi, A.S., J.R.S., B.M.), University of Marburg, Marburg, Germany; Department of Cardiology (K.N.), Saga Medical School, Saga, Japan; Department of Medicine (J.K.L., K.L.) Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass; Roche Genetics and Roche Center for Medical Genomics (K.L.), F. Hoffmann-La Roche Ltd, Basel, Switzerland; and Division of Intramural Research (D.C.Z), NIEHS/NIH, Research Triangle Park, NC.

^* To whom correspondence should be addressed. E-mail: martin.spiecker{at}ruhr-uni-bochum.de.

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.

Methods and 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.

Key words: atherosclerosis • coronary disease • genetics • inflammation • molecular biology

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