Association of rs11780592 Polymorphism in the Human Soluble Epoxide Hydrolase Gene (EPHX2) with Oxidized LDL and Mortality in Patients with Diabetic Chronic Kidney Disease

Abstract

Soluble epoxide hydrolase 2 (EPHX2) is an enzyme promoting increased cellular apoptosis through induction of oxidative stress (OS) and inflammation. The EPHX2 gene which encodes soluble EPHX2 might be implicated in the pathogenesis and development of OS and atherosclerosis. We aimed to assess the possible association between two functional polymorphisms of the EPHX2 gene (rs2741335 and rs11780592) with oxidized LDL (ox-LDL), carotid atherosclerosis, mortality, and cardiovascular (CV) disease in 118 patients with diabetic chronic kidney disease (CKD). At baseline, ox-LDL and carotid intima-media thickness (cIMT) were evaluated and all patients were followed for seven years with outcomes all-cause mortality and CV events. rs11780592 EPHX2 polymorphism was associated with ox-LDL, cIMT, albuminuria, and hypertension. Compared to AG and GG, AA homozygotes had higher values of albuminuria, ox-LDL, and cIMT ( p = 0.046 , p = 0.003 , and p = 0.038 , respectively). These associations remained significant, even after grouping for the G allele. After the follow-up period, 42/118 patients died (30/60 with AA genotype, 11/42 with AG genotype, and 1/12 with GG genotype) and 49/118 experienced a new CV event (fatal or nonfatal). The Kaplan-Meier analysis revealed that patients with the AA genotype exhibited a significantly higher mortality risk, compared to patients with AG and GG genotypes ( p = 0.006 ). This association became even stronger, when AG and GG genotypes were grouped (AA vs. AG/GG, p = 0.002 ). AA homozygotes were strongly associated with all-cause mortality in both univariate (hazard ratio HR = 2.74 , confidence interval CI = 1.40 – 5.35 , p = 0.003 ) and multivariate Cox regression analysis ( HR = 2.61 , CI = 1.32 – 5.17 , p = 0.006 ). In conclusion, our study demonstrated that genetic variations of EPHX2 gene were associated with increased circulating ox-LDL, increased cIMT, and all-cause mortality in diabetic CKD. Since EPHX2 regulates the cholesterol efflux and the oxidation of LDL in foam cells and macrophages, our study suggests that a genetic basis to endothelial dysfunction and OS might be present in diabetic CKD.

Oxidized LDL Is Associated with eGFR Decline in Proteinuric Diabetic Kidney Disease: A Cohort Study

“…In T2DM patients, both ADMA and limited nitric oxide bioavailability, independently from each other, predict micro and macrovascular complications, including onset of DKD [ 23 ]. Moreover, the rs11780592 polymorphism of the soluble epoxide hydrolase 2 (EPHX2), an enzyme triggering cellular apoptosis through induction of OS and inflammation, was associated with ox-LDL, albuminuria, and mortality in a cohort of DKD patients [ 24 ]. But even locally, experimental data suggest that ox-LDL might play a key role in the development of glomerulosclerosis in DKD.…”

An advanced network pharmacology study to explore the novel molecular mechanism of Compound Kushen Injection for treating hepatocellular carcinoma by bioinformatics and experimental verification

“…The EPHX2 gene encodes soluble epoxide hydrolase (sEH), a bifunctional enzyme of the epoxide hydrolase family, an enzyme that promotes increased apoptosis by inducing oxidative stress and inflammation [ 86 ]. Thomassen et al found that sEH degrades biologically active epoxy fatty acids derived from arachidonic acid through the metabolism of P450 cytochromes (CYP) in the arachidonic acid pathway [ 87 ].…”

Soluble Epoxide Hydrolase and Diabetes Complications

“…The rs11780592 polymorphism of Ephx2 (the gene that encodes sEH) has been associated with increased oxidized LDL, carotid intima-media thickness, and mortality in individuals with diabetic chronic kidney disease [ 47 ], suggesting that genetic variants may influence endothelial dysfunction and progression of renal damage in T2DM.…”