Polymorphism of the Soluble Epoxide Hydrolase Is Associated With Coronary Artery Calcification in African-American Subjects

Abstract

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 (Pϭ0.22; Pϭ0.17, 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; Pϭ0.02). 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; Pϭ0.49).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.

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

“…There is little known about the importance of this endogenous system within the heart even though the heart contains significant levels of functionally active CYP. Finally, and most importantly, recent human epidemiological evidence has identified associations between CYP2J2 polymorphisms and CAD, and EPHX2 polymorphisms and CHD [43,45,46,84]. These findings provide strong evidence supporting the notion that EETs play an important role in postischemic functional recovery and perhaps infarct size reduction [31,33,36,83].…”

“…These studies highlight the complexity of the CYP enzyme system, emphasize the role of different CYP metabolites in cardioprotection and suggest caution in the interpretation of results when using non-selective CYP inhibitors. Recent epidemiologic data suggests an association between single nucleotide polymorphisms in the genes encoding CYP2J2, CYP2C8, CYP2C9 and EPHX2 and cardiovascular disease risk in humans supporting the functional relevance of the CYP epoxygenase pathway in the heart [43][44][45][46][47].…”

Microsomal epoxide hydrolase polymorphisms

“…Several polymorphisms in human sEH have been identified, including variants with higher (Lys55Arg) and lower (Arg287Gln) epoxide hydrolase activity (36,37). In recent years, case-control studies examining the sEH polymorphisms in different populations and also the association of these polymorphisms with cardiovascular diseases have been published (38)(39)(40)(41)(42). However, these studies need to be supported by others carried out in different populations; more research is required to confirm this association and to better understand the mechanisms behind it.…”

Cardiorespiratory fitness and coronary artery calcification in young adults: The CARDIA Study

“…Test-retest laboratory reliability coefficients for total cholesterol, HDL-C, LDL-C, and triglycerides were > 0.98 [31]. Additional details of examination procedures are published elsewhere [31][32].…”