Genetic variation in soluble epoxide hydrolase: association with outcome after aneurysmal subarachnoid hemorrhage

Abstract

Object Patients with aneurysmal subarachnoid hemorrhage (SAH) are at high risk for delayed cerebral ischemia (DCI) and stroke. Epoxyeicosatrienoic acids (EETs) play an important role in cerebral blood flow regulation and neuroprotection after brain injury. Polymorphisms in the gene for the enzyme soluble epoxide hydrolase (sEH), which inactivates EETs, are associated with ischemic stroke risk and neuronal survival after ischemia. In this prospective observational study of patients with SAH we compare vital and neurologic outcomes based on functional polymorphisms of sEH. Methods Allelic discrimination based on quantitative real-time PCR was used to differentiate wild type (WT) sEH from K55R heterozygotes (predictive of increased sEH activity and reduced EETs) and R287Q heterozygotes (predictive of decreased sEH activity and increased EETs). The primary outcome was new stroke after SAH. Secondary outcomes were mortality, Glasgow outcome scale (GOS) score and neurologic deterioration attributable to delayed cerebral ischemia (DCI). Results Multivariable logistic regression models adjusted for admission age and Glasgow coma scale revealed an increase in the odds of new stroke (OR 5.48 (1.51–19.91) and mortality (OR 7.62 (1.19–48.7) in the K55R group, but no change in the odds of new stroke 0.56 (0.16–1.96) or death 3.09 (0.51–18.52) in patients with R287Q genotype, compared to wild-type sEH. R287Q genotype was associated with reduced odds of having a GOS ≤ 3 (0.23 (0.06–0.82)). There were no significant differences in the odds of neurologic deterioration due to DCI. Conclusions Genetic polymorphisms of sEH are associated with neurologic and vital outcomes after aneurysmal subarachnoid hemorrhage.

Soluble Epoxide Hydrolase in Hydrocephalus, Cerebral Edema, and Vascular Inflammation After Subarachnoid Hemorrhage

“…Thus it is likely that the benefits of sEH deletion are multifactorial. Overall, these findings complement our previous work demonstrating improved outcomes after SAH in both humans 17 and mice 16 when sEH activity is altered, and support the hypothesis that sEH inhibition may be a viable therapeutic strategy in SAH.…”

“…We have previously demonstrated that mice with elevated levels of EETs due to genetic deletion of their metabolizing enzyme soluble epoxide hydrolase (sEH knockout, sEHKO mice) are protected from experimental cerebral ischemia 15 and delayed microvascular dysfunction 16 after experimental SAH. Further, we have shown that patients with genetic polymorphisms that reduce sEH activity have improved outcomes after SAH 17 . We hypothesized that the beneficial effects of EETs also modulate acute inflammation and edema formation after SAH.…”

18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

“…Various studies have shown that EETs protect the brain during stroke and that inhibition of sEH enhances this effect (10). Patients suffering aneurysmal subarachnoid hemorrhage are at high risk for delayed cerebral ischemia and stroke (11). Patients with the common K55R genetic polymorphism in the sEH gene ( Ephx2 ) demonstrated 30% lower levels of EETs due to increased activity of sEH (12) and they exhibited a mortality of 28.6% after stroke versus 5.3% in the control subjects (11).…”

Cytochrome P450 eicosanoids in cerebrovascular function and disease

“…A study has shown that in patients admitted with aneurysmal SAH (aSAH), those with the Lys55Arg (K55R) polymorphism, predictive of increased sEH activity, had a significantly increased likelihood of experiencing a new stroke compared to patients with the wild-type gene. No difference was observed between patients with Arg287Gln (R287Q), associated with decreased EET metabolism and increased EETs, or wild-type genotypes (Martini et al, 2014); the same pattern was also observed for mortality. However, despite the increased likelihood of stroke in the K55R group, neurological deterioration attributable to DCI is not changed by genotype, though patients with the R287Q polymorphism had a significantly reduced length of hospital stay compared to either K55R or wild-type (Martini et al, 2014).…”

“…No difference was observed between patients with Arg287Gln (R287Q), associated with decreased EET metabolism and increased EETs, or wild-type genotypes (Martini et al, 2014); the same pattern was also observed for mortality. However, despite the increased likelihood of stroke in the K55R group, neurological deterioration attributable to DCI is not changed by genotype, though patients with the R287Q polymorphism had a significantly reduced length of hospital stay compared to either K55R or wild-type (Martini et al, 2014). Sampling CSF after aSAH showed that CYP2C8*4 allele carriers had decreased EETs and DHETs CSF levels, and were over twice as likely to develop DCI and clinical neurologic deterioration, the latter defined in this study as a decrease of two points on the Glasgow Outcome Scale.…”