Genetic Markers in the EET Metabolic Pathway Are Associated with Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage

Abstract

Preclinical studies show that epoxyeicosatrienoic acids (EETs) regulate cerebrovascular tone and protect against cerebral ischemia. We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism, cytochrome P450 (CYP) eicosanoid levels, and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage (aSAH). Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid (DHET) cerebrospinal fluid (CSF) levels, as well as acute outcomes defined by delayed cerebral ischemia (DCI) or clinical neurologic deterioration (CND), were assessed over 14 days. Long-term outcomes were defined by Modified Rankin Scale (MRS) at 3 and 12 months. CYP2C8*4 allele carriers had 44% and 36% lower mean EET and DHET CSF levels (P=0.003 and P=0.007) and were 2.2- and 2.5-fold more likely to develop DCI and CND (P=0.039 and P=0.041), respectively. EPHX2 55Arg, CYP2J2*7, CYP2C8*1B, and CYP2C8 g.36785A allele carriers had lower EET and DHET CSF levels. CYP2C8 g.25369T and CYP2C8 g.36755A allele carriers had higher EET levels. Patients with CYP2C8*2C and EPHX2 404del variants had worse long-term outcomes while those with EPHX2 287Gln, CYP2J2*7, and CYP2C9 g.816G variants had favorable outcomes. Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes. Dihydroxyeicosatetraenoic acids were not associated with outcomes. No associations passed Bonferroni multiple testing correction. These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH.

Cytochrome P450 eicosanoids in cerebrovascular function and disease

“…Generally these studies correlate with the animal studies, indicating that decreased sEH and increased EET may be beneficial after SAH. There is however a great degree of genetic variation in the EETs pathway; genes involved in either EETs generation or breakdown may contribute in different degrees to the clinical outcomes observed (Donnelly et al, 2015)…”

Optimizing Medication Outcomes in Neurocritical Care: Focus on Clinical Pharmacology

“…Preliminary biomarker information is being reported for investigational vasospasm treatments. 107,108 Endothelin-1 gene polymorphisms have been described in the CSF after aneurysmal SAH. The ET-1 levels were associated with angiographic vasospasm, and the biomarker, 20 HETE concentrations were associated with delayed cerebral ischemia and poor outcomes.…”

“…Epoxy-icosatrienoic acids (EETS) regulate cerebrovascular tone and protect against cerebral ischemia. 107,108 These biomarkers were measured in CSF within 14 days of SAH and were associated with higher Fisher grade and unfavorable 3-month outcomes. Glial fibrillary acidic protein (GFAP) is a biomarker for both simvastatin and levetiracetam in a TBI model.…”

A comprehensive study revealed SNP–SNP interactions and a sex-dependent relationship between polymorphisms of the CYP2J2 gene and hypertension risk

“…Cytochrome P-450 2J2 (CYP2J2), a major enzyme of the epoxygenase pathway in the heart and vasculature, meta bolizes AA to all four regioisomeric cis-EETs, including 5,6-, 8,9-, 11,12-and 14,15-EETs [10,[13][14][15]. Taking into account the multifaceted cardiovascular and renal actions of EETs, single nucleotide polymorphisms (SNP) of the CYP2J2 gene have become the targets for genetic association studies of cardiovascular disorders in various populations [16][17][18][19][20][21][22][23][24][25][26][27]. However, a limited number of studies has been conducted to date to investigate the contribution of CYP2J2 gene polymorphisms to hypertension suscept ibility [28][29][30][31][32][33].…”