Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study

Epoxide hydrolase is involved in metabolism of vasoactive and anti-inflammatory epoxyeicosatrienoic acids to their corresponding diols. Consequently, epoxide hydrolase 2 (EPHX2) is a candidate cardiovascular disease (CVD) gene. We investigated EPHX2 for association with subclinical CVD in European American (EA) and African American (AA) families from the Diabetes Heart Study. The R287Q polymorphism was associated with carotid artery calcified plaque (CarCP) in EAs. Other EPHX2 polymorphisms were associated with coronary artery calcified plaque (CorCP), CarCP or carotid artery intima-media thickness (IMT). Polymorphism rs7837347 was associated with all traits in the AAs (p=0.003, 0.001 and 0.017, respectively). Polymorphism rs7003694 displayed association with IMT (p=0.017) and, along with rs747276, a trend towards association with CorCP in diabetic EAs (p=0.057 and 0.080, respectively). These results provide additional evidence that EPHX2 contributes to the risk of subclinical CVD, although the true trait defining polymorphisms may not be identified and the effect size could be small.

[1]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[2]  M. Fornage,et al.  Sequence variation in the soluble epoxide hydrolase gene and subclinical coronary atherosclerosis: interaction with cigarette smoking. , 2007, Atherosclerosis.

[3]  M. Fornage,et al.  Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. , 2006, Human molecular genetics.

[4]  S. Gabriel,et al.  Efficiency and power in genetic association studies , 2005, Nature Genetics.

[5]  M. Fornage,et al.  The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. , 2005, Human molecular genetics.

[6]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[7]  C. Langefeld,et al.  Race-Specific Relationships Between Coronary and Carotid Artery Calcification and Carotid Intimal Medial Thickness , 2004, Stroke.

[8]  M. Fornage,et al.  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 , 2004, Circulation.

[9]  C. Langefeld,et al.  Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster. , 2003, Genomics.

[10]  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.

[11]  J. Hardin,et al.  Generalized Estimating Equations , 2002 .

[12]  C. Langefeld,et al.  Heritability of Carotid Artery Intima-Medial Thickness in Type 2 Diabetes , 2002, Stroke.

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

[14]  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.

[15]  C. Langefeld,et al.  Familial aggregation of coronary artery calcium in families with type 2 diabetes. , 2001, Diabetes.

[16]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .

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

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

[19]  P. Pratt,et al.  Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. , 1996, Circulation research.

[20]  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.

[21]  Y. Hochberg.  A sharper Bonferroni procedure for multiple tests of significance , 1988 .

[22]  A. Dyer,et al.  Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women. , 1986, American journal of epidemiology.

[23]  K Y Liang,et al.  Longitudinal data analysis for discrete and continuous outcomes. , 1986, Biometrics.

[24]  R. Estabrook,et al.  The reaction of arachidonic acid epoxides (epoxyeicosatrienoic acids) with a cytosolic epoxide hydrolase. , 1983, Archives of biochemistry and biophysics.

[25]  D L McGee,et al.  Diabetes and Glucose Tolerance as Risk Factors for Cardiovascular Disease: The Framingham Study , 1979, Diabetes Care.