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

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  • 1 Departments of Anesthesiology & Perioperative Medicine and
  • 2 Neurological Surgery, Oregon Health & Science University; and
  • 3 Portland Veterans Affairs Medical Center, Portland, Oregon
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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. This prospective observational study of patients with SAH compares vital and neurologic outcomes based on functional polymorphisms of sEH.

Methods

Allelic discrimination based on quantitative real-time polymerase chain reaction was used to differentiate wild-type 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 death, Glasgow Outcome Scale score, and neurological deterioration attributable to DCI.

Results

Multivariable logistic regression models adjusted for age at admission and Glasgow Coma Scale scores revealed an increase in the odds of new stroke (OR 5.48 [95% CI 1.51–19.91]) and death (OR 7.52 [95% CI 1.27–44.46]) in the K55R group, but no change in the odds of new stroke (OR 0.56 [95% CI 0.16–1.96]) or death (OR 3.09 [95% CI 0.51–18.52]) in patients with R287Q genotype, compared with wild-type sEH. The R287Q genotype was associated with reduced odds of having a Glasgow Outcome Scale score of ≤ 3 (OR 0.23 [95% CI 0.06–0.82]). There were no significant differences in the odds of neurological deterioration due to DCI.

Conclusions

Genetic polymorphisms of sEH are associated with neurological and vital outcomes after aneurysmal SAH.

Abbreviations used in this paper:ARDS = acute respiratory distress syndrome; CBF = cerebral blood flow; CSW = cerebral salt wasting; DCI = delayed cerebral ischemia; EET = epoxyeicosatrienoic acid; EVD = extraventricular drain; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; ICU = intensive care unit; IQR = interquartile range; qPCR = quantitative polymerase chain reaction; SAH = subarachnoid hemorrhage; SAPS II = Simplified Acute Physiology Score; sEH = soluble epoxide hydrolase; SIADH = syndrome of inappropriate secretion of antidiuretic hormone; TCD = transcranial Doppler; WBC = white blood cell; WT = wild type.

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Contributor Notes

Address correspondence to: Justin S. Cetas, M.D., Ph.D., Department of Neurological Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. email: cetasj@ohsu.edu.

Please include this information when citing this paper: published online September 12, 2014; DOI: 10.3171/2014.7.JNS131990.

  • 1

    Abdu E, , Bruun DA, , Yang D, , Yang J, , Inceoglu B, & Hammock BD, : Epoxyeicosatrienoic acids enhance axonal growth in primary sensory and cortical neuronal cell cultures. J Neurochem 117:632642, 2011

    • Search Google Scholar
    • Export Citation
  • 2

    Anandan SK, , Webb HK, , Chen D, , Wang YX, , Aavula BR, & Cases S, : 1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia. Bioorg Med Chem Lett 21:983988, 2011

    • Search Google Scholar
    • Export Citation
  • 3

    Diringer MN, , Bleck TP, , Claude Hemphill J III, , Menon D, , Shutter L, & Vespa P, : Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit Care 15:211240, 2011

    • Search Google Scholar
    • Export Citation
  • 4

    Dreier JP, , Drenckhahn C, , Woitzik J, , Major S, , Offenhauser N, & Weber-Carstens S, : Spreading ischemia after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 115:125129, 2013

    • Search Google Scholar
    • Export Citation
  • 5

    Fava C, , Montagnana M, , Danese E, , Almgren P, , Hedblad B, & Engström G, : Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes. Pharmacogenet Genomics 20:94103, 2010

    • Search Google Scholar
    • Export Citation
  • 6

    Fitzpatrick FA, , Ennis MD, , Baze ME, , Wynalda MA, , McGee JE, & Liggett WF: Inhibition of cyclooxygenase activity and platelet aggregation by epoxyeicosatrienoic acids. Influence of stereochemistry. J Biol Chem 261:1533415338, 1986

    • Search Google Scholar
    • Export Citation
  • 7

    Fleming I: Epoxyeicosatrienoic acids, cell signaling and angiogenesis. Prostaglandins Other Lipid Mediat 82:6067, 2007

  • 8

    Fornage M, , Lee CR, , Doris PA, , Bray MS, , Heiss G, & Zeldin DC, : The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. Hum Mol Genet 14:28292837, 2005

    • Search Google Scholar
    • Export Citation
  • 9

    Gschwendtner A, , Ripke S, , Freilinger T, , Lichtner P, , Müller-Myhsok B, & Wichmann HE, : Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans. Stroke 39:15931596, 2008

    • Search Google Scholar
    • Export Citation
  • 10

    Iliff JJ, & Alkayed NJ: Soluble epoxide hydrolase inhibition: targeting multiple mechanisms of ischemic brain injury with a single agent. Future Neurol 4:179199, 2009

    • Search Google Scholar
    • Export Citation
  • 11

    Iliff JJ, , Wang R, , Zeldin DC, & Alkayed NJ: Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels. Am J Physiol Heart Circ Physiol 296:H1352H1363, 2009

    • Search Google Scholar
    • Export Citation
  • 12

    Kasius KM, , Frijns CJ, , Algra A, & Rinkel GJ: Association of platelet and leukocyte counts with delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis 29:576583, 2010

    • Search Google Scholar
    • Export Citation
  • 13

    Kilbourn KJ, , Levy S, , Staff I, , Kureshi I, & McCullough L: Clinical characteristics and outcomes of neurogenic stress cadiomyopathy in aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 115:909914, 2013

    • Search Google Scholar
    • Export Citation
  • 14

    Koehler RC, , Roman RJ, & Harder DR: Astrocytes and the regulation of cerebral blood flow. Trends Neurosci 32:160169, 2009

  • 15

    Koerner IP, , Jacks R, , DeBarber AE, , Koop D, , Mao P, & Grant DF, : Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J Neurosci 27:46424649, 2007

    • Search Google Scholar
    • Export Citation
  • 16

    Koerner IP, , Zhang W, , Cheng J, , Parker S, , Hurn PD, & Alkayed NJ: Soluble epoxide hydrolase: regulation by estrogen and role in the inflammatory response to cerebral ischemia. Front Biosci 13:28332841, 2008

    • Search Google Scholar
    • Export Citation
  • 17

    Le Gall JR, , Lemeshow S, & Saulnier F: A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 270:29572963, 1993

    • Search Google Scholar
    • Export Citation
  • 18

    Lee CR, , North KE, , Bray MS, , Fornage M, , Seubert JM, & Newman JW, : Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Hum Mol Genet 15:16401649, 2006

    • Search Google Scholar
    • Export Citation
  • 19

    Lysakowski C, , Walder B, , Costanza MC, & Tramèr MR: Transcranial Doppler versus angiography in patients with vasospasm due to a ruptured cerebral aneurysm: a systematic review. Stroke 32:22922298, 2001

    • Search Google Scholar
    • Export Citation
  • 20

    Rabinstein AA, , Friedman JA, , Weigand SD, , McClelland RL, , Fulgham JR, & Manno EM, : Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 35:18621866, 2004

    • Search Google Scholar
    • Export Citation
  • 21

    Rabinstein AA, & Sandhu K: Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J Neurol Neurosurg Psychiatry 78:12781280, 2007

    • Search Google Scholar
    • Export Citation
  • 22

    Roos YB, , de Haan RJ, , Beenen LF, , Groen RJ, , Albrecht KW, & Vermeulen M: Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry 68:337341, 2000

    • Search Google Scholar
    • Export Citation
  • 23

    Rowland MJ, , Hadjipavlou G, , Kelly M, , Westbrook J, & Pattinson KT: Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth 109:315329, 2012

    • Search Google Scholar
    • Export Citation
  • 24

    Sandberg M, , Hassett C, , Adman ET, , Meijer J, & Omiecinski CJ: Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms. J Biol Chem 275:2887328881, 2000

    • Search Google Scholar
    • Export Citation
  • 25

    Spector AA, , Fang X, , Snyder GD, & Weintraub NL: Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog Lipid Res 43:5590, 2004

    • Search Google Scholar
    • Export Citation
  • 26

    Srivastava PK, , Sharma VK, , Kalonia DS, & Grant DF: Polymorphisms in human soluble epoxide hydrolase: effects on enzyme activity, enzyme stability, and quaternary structure. Arch Biochem Biophys 427:164169, 2004

    • Search Google Scholar
    • Export Citation
  • 27

    Uhl E, , Lehmberg J, , Steiger HJ, & Messmer K: Intraoperative detection of early microvasospasm in patients with subarachnoid hemorrhage by using orthogonal polarization spectral imaging. Neurosurgery 52:13071317, 2003

    • Search Google Scholar
    • Export Citation
  • 28

    Vergouwen MD, , Ilodigwe D, & Macdonald RL: Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke 42:924929, 2011

    • Search Google Scholar
    • Export Citation
  • 29

    Vergouwen MD, , Vermeulen M, , Coert BA, , Stroes ES, & Roos YB: Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab 28:17611770, 2008

    • Search Google Scholar
    • Export Citation
  • 30

    Vergouwen MD, , Vermeulen M, , van Gijn J, , Rinkel GJ, , Wijdicks EF, & Muizelaar JP, : Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:23912395, 2010

    • Search Google Scholar
    • Export Citation
  • 31

    Zhang L, , Ding H, , Yan J, , Hui R, , Wang W, & Kissling GE, : Genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in a Chinese population. Pharmacogenet Genomics 18:4551, 2008

    • Search Google Scholar
    • Export Citation
  • 32

    Zhang W, , Koerner IP, , Noppens R, , Grafe M, , Tsai HJ, & Morisseau C, : Soluble epoxide hydrolase: a novel therapeutic target in stroke. J Cereb Blood Flow Metab 27:19311940, 2007

    • Search Google Scholar
    • Export Citation
  • 33

    Zhang W, , Otsuka T, , Sugo N, , Ardeshiri A, , Alhadid YK, & Iliff JJ, : Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia. Stroke 39:20732078, 2008

    • Search Google Scholar
    • Export Citation

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