Polymorphism of the Soluble Epoxide Hydrolase Is Associated With Coronary Artery Calcification in African-American Subjects: The Coronary Artery Risk Development In Young Adults (CARDIA) Study

Background—Modulation of endogenous epoxide levels by soluble epoxide hydrolase (sEH) in the endothelium represents an important mechanism in the regulation of cardiovascular function. We examined the relationship between a common, functional polymorphism of the human sEH gene and coronary artery calcification (CAC) in young, largely asymptomatic African-American and non-Hispanic white subjects. Methods and Results—Multiple logistic regression and Tobit regression models were used to assess the relationship between the sEH Arg287Gln polymorphism and presence and quantity of CAC. Models adjusting for race (except in race-specific analyses), age, sex, smoking, body mass index, systolic blood pressure, LDL cholesterol, and HDL cholesterol were estimated. Allele and genotype frequency distributions were not significantly different between the 2 ethnic groups (P =0.22; P =0.17, respectively). The Arg287Gln polymorphism of the sEH gene was a significant predictor of CAC status in African-American participants, either alone or after adjusting for other risk factors. African-American subjects with at least 1 copy of the Gln287 allele had a 2-fold greater risk of having CAC compared with those not carrying this allele (95% CI, 1.1 to 2.9; P =0.02). There was no relationship between Arg287Gln polymorphism and the probability of having CAC in white participants (OR, 0.8; 95% CI, 0.5 to 1.3; P =0.49). Inferences from multivariable Tobit regression were similar to those obtained in the logistic regression models, indicating that the Arg287Gln polymorphism was a significant independent predictor of both presence and quantity of CAC in African-American but not white subjects. Conclusions—These data suggest an intriguing and possibly novel role for sEH in the pathogenesis of atherosclerosis, which deserves additional investigation.

[1]  F. Oesch,et al.  The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  B. Hammock,et al.  The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Detrano The ethnic-specific nature of mechanisms for coronary heart disease. , 2003, Journal of the American College of Cardiology.

[4]  P. O'Malley,et al.  The prevalence and severity of coronary artery calcification on coronary artery computed tomography in black and white subjects. , 2003, Journal of the American College of Cardiology.

[5]  B. Hammock,et al.  Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide. , 2002, American journal of physiology. Heart and circulatory physiology.

[6]  M. Fornage,et al.  Polymorphism in Soluble Epoxide Hydrolase and Blood Pressure in Spontaneously Hypertensive Rats , 2002, Hypertension.

[7]  M. W. Foster,et al.  Race, ethnicity, and genomics: social classifications as proxies of biological heterogeneity. , 2002, Genome research.

[8]  L. Kuller,et al.  Racial Differences in Coronary Artery Calcification in Older Adults , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[9]  D. Thompson,et al.  Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. Roman,et al.  P-450 metabolites of arachidonic acid in the control of cardiovascular function. , 2002, Physiological reviews.

[11]  R. Cooper,et al.  Commentary: considerations for use of racial/ethnic classification in etiologic research. , 2001, American journal of epidemiology.

[12]  D. Thompson,et al.  Pathways of Epoxyeicosatrienoic Acid Metabolism in Endothelial Cells , 2001, The Journal of Biological Chemistry.

[13]  F. Gonzalez,et al.  Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation* , 2000, The Journal of Biological Chemistry.

[14]  B D Hammock,et al.  Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids , 2000, Circulation research.

[15]  Y. Arad,et al.  Prediction of coronary events with electron beam computed tomography. , 2000, Journal of the American College of Cardiology.

[16]  J. Meijer,et al.  Identification and Functional Characterization of Human Soluble Epoxide Hydrolase Genetic Polymorphisms* , 2000, The Journal of Biological Chemistry.

[17]  J. Gardin,et al.  Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. , 2000, The American journal of cardiology.

[18]  J. Rumberger,et al.  Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography calcium score strata. , 2000, Circulation.

[19]  R. Detrano,et al.  Prognostic value of coronary electron-beam computed tomography for coronary heart disease events in asymptomatic populations. , 2000, The American journal of cardiology.

[20]  A. Schmermund,et al.  Potential and pitfalls of electron-beam computed tomography in detecting coronary atherosclerosis , 1999, Basic Research in Cardiology.

[21]  X. Fang,et al.  Epoxyeicosatrienoic acids increase intracellular calcium concentration in vascular smooth muscle cells. , 1999, Hypertension.

[22]  R. Busse,et al.  Cytochrome P450 2C is an EDHF synthase in coronary arteries , 1999, Nature.

[23]  K. Bailey,et al.  Independent and incremental value of coronary artery calcium for predicting the extent of angiographic coronary artery disease: comparison with cardiac risk factors and radionuclide perfusion imaging. , 1999, Journal of the American College of Cardiology.

[24]  R. Detrano,et al.  Racial differences in the significance of coronary calcium in asymptomatic black and white subjects with coronary risk factors. , 1999, Journal of the American College of Cardiology.

[25]  K. Ley,et al.  Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. , 1999, Science.

[26]  N. Weintraub,et al.  Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation. , 1998, Circulation research.

[27]  W. Graier,et al.  ORIGIN AND FUNCTION OF EPOXYEICOSATRIENOIC ACIDS IN VASCULAR ENDOTHELIAL CELLS: MORE THAN JUST ENDOTHELIUM‐DERIVED HYPERPOLARIZING FACTOR? , 1998, Clinical and experimental pharmacology & physiology.

[28]  Y. Arad,et al.  Predictive value of EBCT scanning. , 1998, Circulation.

[29]  A. A. Spector,et al.  Potentiation of endothelium-dependent relaxation by epoxyeicosatrienoic acids. , 1997, Circulation research.

[30]  B. Hammock,et al.  Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase , 1997, Nature Medicine.

[31]  L. Navar,et al.  Actions of epoxygenase metabolites on the preglomerular vasculature. , 1996, Journal of the American Society of Nephrology : JASN.

[32]  H. Knapp,et al.  Arachidonic Acid Diols Produced by Cytochrome P-450 Monooxygenases Are Incorporated into Phospholipids of Vascular Endothelial Cells* , 1996, The Journal of Biological Chemistry.

[33]  M. Budoff,et al.  Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. , 1996, Journal of the American College of Cardiology.

[34]  R. Detrano,et al.  Racial differences in coronary calcium prevalence among high-risk adults. , 1995, The American journal of cardiology.

[35]  M. Karmazyn,et al.  Effects of epoxyeicosatrienoic acids on isolated hearts and ventricular myocytes. , 1993, The American journal of physiology.

[36]  R. Estabrook,et al.  Cytochrome P450 and the arachidonate cascade 1 , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  E. Ellis,et al.  14,15‐Epoxyeicosatrienoic Acid Inhibits Platelet Aggregation in Mouse Cerebral Arterioles , 1991, Stroke.

[38]  R. Detrano,et al.  Quantification of coronary artery calcium using ultrafast computed tomography. , 1990, Journal of the American College of Cardiology.

[39]  S B Hulley,et al.  CARDIA: study design, recruitment, and some characteristics of the examined subjects. , 1988, Journal of clinical epidemiology.

[40]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[41]  J. Mcnamara,et al.  Coronary artery disease in combat casualties in Vietnam. , 1971, JAMA.