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Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study.

ABSTRACT: Epoxide hydrolase is involved in metabolism of vasoactive and anti-inflammatory epoxyeicosatrienoic acids to their corresponding diols. Consequently, epoxide hydrolase 2 (EPHX2) is a candidate cardiovascular disease (CVD) gene. We investigated EPHX2 for association with subclinical CVD in European American (EA) and African American (AA) families from the Diabetes Heart Study. The R287Q polymorphism was associated with carotid artery calcified plaque (CarCP) in EAs. Other EPHX2 polymorphisms were associated with coronary artery calcified plaque (CorCP), CarCP or carotid artery intima-media thickness (IMT). Polymorphism rs7837347 was associated with all traits in the AAs (p=0.003, 0.001 and 0.017, respectively). Polymorphism rs7003694 displayed association with IMT (p=0.017) and, along with rs747276, a trend towards association with CorCP in diabetic EAs (p=0.057 and 0.080, respectively). These results provide additional evidence that EPHX2 contributes to the risk of subclinical CVD, although the true trait defining polymorphisms may not be identified and the effect size could be small.

SUBMITTER: Burdon KP

PROVIDER: S-EPMC4882928 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study.

Burdon Kathryn P KP Lehtinen Allison B AB Langefeld Carl D CD Carr J Jeffrey JJ Rich Stephen S SS Freedman Barry I BI Herrington David D Bowden Donald W DW

Diabetes & vascular disease research 20080601 2

Epoxide hydrolase is involved in metabolism of vasoactive and anti-inflammatory epoxyeicosatrienoic acids to their corresponding diols. Consequently, epoxide hydrolase 2 (EPHX2) is a candidate cardiovascular disease (CVD) gene. We investigated EPHX2 for association with subclinical CVD in European American (EA) and African American (AA) families from the Diabetes Heart Study. The R287Q polymorphism was associated with carotid artery calcified plaque (CarCP) in EAs. Other EPHX2 polymorphisms were ...[more]

PMID: 18537101

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Project description:Background Single nucleotide polymorphisms (SNPs) in the EPHX2 gene have been implicated in susceptibility to cardiovascular diseases, including coronary heart disease (CHD). EPHX2 encodes for soluble epoxide hydrolase, an important enzyme involved in the metabolic breakdown of arachidonic acid-derived vasoactive and anti-inflammatory eicosanoids referred to as epoxyeicosatrienoic acids to their corresponding diols. Our pilot study aimed to investigate whether common SNPs such as rs751141, rs4149253, and rs1042064 of the EPHX2 gene are associated with susceptibility to CHD in Russian population. Methods A total of 1,183 unrelated Russian subjects comprising 602 patients with angiographically diagnosed CHD and 581 age- and sex-matched healthy subjects were recruited and their DNA samples were genotyped for the selected SNPs using a high-throughput Mass-ARRAY genotyping platform. Results No significant associations were found between the investigated SNPs and CHD risk (P>0.05). A polymorphism rs751141 (amino acid substitution, R287Q) displayed a trend towards association with CHD (odds ratio adjusted by sex and age was 3.02, 95% CI: 0.97–9.43, P correction =0.16). SNP-smoking interaction analyses did not identify synergic effects of the studied SNPs and cigarette smoking on the disease risk (P>0.05). A linkage disequilibrium was found between SNPs rs751141 and rs4149253 (D’ =0.995), rs751141 and rs1042064 (D’ =0.967), rs4149253 and rs1042064 (D’ =0.965). Four common haplotypes G-G-T (73%), A-G-C (10%), G-G-C (9%) and G-A-C (7%) have been identified, however, none of them showed a significant association with the risk of CHD in the studied population (P>0.05). Conclusions The investigated polymorphisms do not contribute to CHD susceptibility in our population. Nevertheless, because of a limited number of SNPs was investigated in this study, definitive conclusions yet to be made in further studies on the contribution of the EPHX2 gene to the development of CHD in Russians.

Project description: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.

Dataset Information

Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study.

Publications

Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study.

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