Genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in a Chinese population

Department of Internal Medicine, The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Pharmacogenetics and Genomics (Impact Factor: 3.48). 02/2008; 18(1):45-51. DOI: 10.1097/FPC.0b013e3282f313e8
Source: PubMed

ABSTRACT Epoxyeicosatrienoic acids have been recognized for their protective effects on the cardiovascular system. This study investigated whether two common polymorphisms in genes believed to be influential in regulating circulating levels of epoxyeicosatrienoic acids, namely cytochrome P450 2J2 (CYP2J2) G-50T and soluble epoxide hydrolase (EPHX2) G860A, were associated with ischemic stroke risk in a Chinese population.
Screening of 200 patients with ischemic stroke and 350 control participants revealed that CYP2J2-50T allele frequency was not significantly different in ischemic stroke cases versus controls. In contrast, EPHX2 860A allele frequency was 16.8% in ischemic stroke cases versus 21.7% in controls (P=0.047), and the presence of this variant allele was associated with a significantly lower risk of ischemic stroke after adjustment for sex, age and multiple cardiovascular risk factors (adjusted odds ratio=0.50, 95% confidence interval 0.29-0.86). Moreover, there was a significant interaction between the EPHX2 G860A polymorphism, smoking and ischemic stroke risk such that nonsmokers carrying the EPHX2 G860A variant allele were at the lowest risk of ischemic stroke (odds ratio=0.33, 95% confidence interval, 0.17-0.67, P=0.002), whereas no significant association was observed in smokers.
Collectively, these data indicate a protective influence of the G860A polymorphism of EPHX2 on ischemic stroke in Chinese nonsmokers.

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    ABSTRACT: Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). Genetic variations in the sEH gene, designated EPHX2, are associated with ischemic stroke risk. In experimental studies, sEH inhibition and gene deletion reduce infarct size after focal cerebral ischemia in mice. Although the precise mechanism of protection afforded by sEH inhibition remains under investigation, EETs exhibit a wide array of potentially beneficial actions in stroke, including vasodilation, neuroprotection, promotion of angiogenesis and suppression of platelet aggregation, oxidative stress and post-ischemic inflammation. Herein we argue that by capitalizing on this broad protective profile, sEH inhibition represents a prototype "combination therapy" targeting multiple mechanisms of stroke injury with a single agent.
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