Lower Risk Of Ischemic Stroke Associated With The Synergism Of Variation In Cytochrome P450 Epoxygenase 2J2 And Soluble Epoxide Hydrolase Genes

Objective:Cytochrome P450 epoxygenases catalyse arachidonic acid to produce 5,6-, 8,9-, 11, 12-, 14,15-EET (epoxyeicosatrienoic acids). EETs are mainly catalysed by the soluble epoxide hydrolase to their corresponding diols. EETs have diverse biological effects in the cardiovascular systems, including anti-inflammation, inhibiting SMC migration and proliferation, increasing fibrinolytic activity. They play an important role in the regulation of local microcirculation. Ischemic stroke is a interactional disease of multiple genes with environmental factors, which relative gene screening and allied-analysis is a hotpoint for research of molecular mechanisms of ischemic stroke. Here, we investigated whether the polymorphism of the CYP2J2 and EPHX2 gene is associated with ischemic stroke in China Han population.Methods:Two hundred cases of ischemic stroke were serially collected from several medical units in Dec. 2000-Jan. 2003, which were confirmed by a computed tomograghy or MRI of the brain. At the same time, three hundred fifty control subjects were healthy subjects from medical examination matched with age and sex. The two polymorphism sites in 200 cases of ischemic stroke and 350 controls for the CYP2J2 G-50T and EPHX2 G860A were analyzed by using polymerase chain-restriction fragment length polymorphisms. The influence of confounding factors was rectified using multivariate Logistic regression model and the interaction among polymorphism on the risk of ischemic stroke was assessed.Results: 1. The T allele of CYP2J2 G-50T polymorphism is 5.3% in ischemic stroke vs 4.3% in control subjects(P=0.45). No -50TT genotype was found in the cases and control subjects.2. The A allele of the EPHX2 G860A polymorphism is 16.8% in ischemic stroke vs 21.7% in control subjects (P=0.047).3. The association of the A allele of the EPHX2 G860A polymorphism with ischemic stroke is still significant after adjustment for gender, age and multiple cardiovascular risk factors (OR=0.484; 95% CI, 0.244 to 0.96; P =0.038).4. Frequency of CYP2J2 and EPHX2 allied-genotype CYP2J2 -50GG/EPHX2 860GG,-50GG/860A+,-50GT/860GG,-50GT/860A+ is 56.3%,35.4%,6%,2.3% in the control vs 65%,25.5% (P =0.018),6.5% (P >0.05),3% (P >0.05) in the cases, which suggests that combined genotype of -50GG/860A+ may be associated with ischemic stroke.5. Further analysis showed that the combined genotype is lower in the Odds ratio after adjustment by using the above cardiovascular risk factors (OR=0.402; 95% CI, 0.194 to 0.833) than the single A allele of EPHX2 G860A (OR=0.484; 95% CI, 0.244 to 0.96; P =0.014).Conclusions:These results of the polymorphism analysis of CYP2J2 and EPHX2 gene showed that CYP2J2 G-50T polymorphism has no significant association with ischemic stroke, but the A allele of EPHX2 G860A for genetic variants (EPHX2 860A+ carriers) show protective effect for ischemic stroke. Importantly, even though CYP2J2 G-50T polymorphism has no significant association with ischemic stroke, co-effect of CYP2J2 -50GG and EPHX2 860A+ genotype combination showed lower risk of ischemic stroke than the single A allele of EPHX2 G860A after adjustment of the gender, age, multiple cardiovascular risk factors in the China Han population.