Article

The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
Human Molecular Genetics (Impact Factor: 6.39). 11/2005; 14(19):2829-37. DOI: 10.1093/hmg/ddi315
Source: PubMed

ABSTRACT

Stroke is the leading cause of severe disability and the third leading cause of death, accounting for one of every 15 deaths
in the USA. We investigated the association of polymorphisms in the soluble epoxide hydrolase gene (EPHX2) with incident ischemic stroke in African-Americans and Whites. Twelve single nucleotide polymorphisms (SNPs) spanning EPHX2 were genotyped in a case-cohort sample of 1336 participants from the Atherosclerosis Risk in Communities (ARIC) study. In
each racial group, Cox proportional hazard models were constructed to assess the relationship between incident ischemic stroke
and EPHX2 polymorphisms. A score test method was used to investigate the association of common haplotypes of the gene with risk of
ischemic stroke. In African-Americans, two common EPHX2 haplotypes with significant and opposing relationships to ischemic stroke risk were identified. In Whites, two common haplotypes
showed suggestive indication of an association with ischemic stroke risk but, as in African-Americans, these relationships
were in opposite direction. These findings suggest that multiple variants exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence; some associated with a higher incidence and others
with a lower incidence.

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    • "Three SNPs (SNP 9, SNP 14 and SNP 23) of EPHX2 showed a significant association with an increased risk of ischemic stroke REVIEW in European patients in the ARIC study (Gschwendtner et al. 2008). Interestingly, two common EPHX2 haplotypes showed apparent and opposing relationships of an association with ischemic stroke risk both in African-Americans and Whites, with one haplotype showed a significantly lower risk of ischemic stroke and another showed higher (Fornage et al. 2005). Taken together, a number of genetic studies have suggested that EPHX2 could be a potential candidate gene for cardiovascular diseases. "
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    • "It was shown that the association of polymorphisms within the EPHX2 gene with cardiovascular risks strongly depends on the ethnical background of the analysed populations [26,35]. Indeed, the reported association could only be observed in Caucasian CHD cases and not in African-Americans. "
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    • "with stroke incidence, with some haplotypes associating with increased and others with decreased stroke risk (Fornage et al., 2005). Polymorphisms in human EPHX2 have also been shown to alter EET conversion by purified sEH in vitro (Przybyla- Zawislak et al., 2003). "
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the human EPHX2 gene have recently been implicated in susceptibility to cardiovascular disease, including stroke. EPHX2 encodes for soluble epoxide hydrolase (sEH), an important enzyme in the metabolic breakdown of arachidonic acid-derived eicosanoids referred to as epoxyeicosatrienoic acids (EETs). We previously demonstrated that EETs are protective against ischemic cell death in culture. Therefore, we tested the hypothesis that polymorphisms in the human EPHX2 gene alter sEH enzyme activity and affect neuronal survival after ischemic injury in vitro. Human EPHX2 mutants were recreated by site-directed mutagenesis and fused downstream of TAT protein transduction domain. Western blot analysis and immunocytochemistry staining revealed high-transduction efficiency of human TAT-sEH variants in rat primary cultured cortical neurons, associated with increased metabolism of 14,15-EET to corresponding 14,15-dihydroxyeicosatrienoic acid. A human variant of sEH with Arg103Cys amino acid substitution, previously demonstrated to increase sEH enzymatic activity, was associated with increased cell death induced in cortical neurons by oxygen-glucose deprivation (OGD) and reoxygenation. In contrast, the Arg287Gln mutation was associated with reduced sEH activity and protection from OGD-induced neuronal cell death. We conclude that sequence variations in the human EPHX2 gene alter susceptibility to ischemic injury and neuronal survival in a manner linked to changes in the hydrolase activity of the enzyme. The findings suggest that human EPHX2 mutations may in part explain the genetic variability in sensitivity to ischemic brain injury and stroke outcome.
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