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.
Highlights
Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are conditions with growing incidence and prevalence worldwide, characterized by high cardiovascular (CV) morbidity and increased mortality [1]
Compared to AG and GG, AA homozygotes had higher values of both urine albumin to creatinine ratio (UACR) and carotid intima-media thickness (cIMT) (p = 0:046 and p = 0:038, respectively). oxidized low-density cholesterol (LDL) (ox-LDL) differed significantly among rs11780592 genotypes in G1/G2 and G4 stages of diabetic CKD, whereas cIMT was significantly higher in AA homozygotes in stages G4 and G5 (Supplementary Table 4)
In a cohort of 118 patients with established diabetic CKD, we found a strong association between cIMT and rs11780592 EPHX2 polymorphism. cIMT is a well-established surrogate marker for endothelial dysfunction and subclinical atherosclerosis in CKD patients and has been associated with mortality and CV disease in a population similar to ours [16] and patients undergoing maintenance HD [23]
Summary
Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are conditions with growing incidence and prevalence worldwide, characterized by high cardiovascular (CV) morbidity and increased mortality [1]. In end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (HD), T2DM contributes to a 1.6-fold increase in the overall mortality risk [4]. This heavy atherogenic and CV burden of diabetic CKD and ESRD cannot be solely explained by traditional risk factors. Oxidative stress (OS), defined as the disruption of balance between prooxidant and antioxidant molecules in favor of the former, has emerged as a novel risk factor for the onset and development of atherosclerosis and CV disease in CKD patients. It is known that the oxidative modification of low-density cholesterol (LDL) is the first crucial step leading to endothelial dysfunction, the hallmark of atherosclerosis [8]
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