Missense Genetic Polymorphisms of Microsomal (EPHX1) and Soluble Epoxide Hydrolase (EPHX2) and Their Relation to the Risk of Large Artery Atherosclerotic Ischemic Stroke in a Turkish Population

Abstract

Purpose Soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH) both catalyze the metabolism of epoxyeicosatrienoic acids (EETs), lipid signaling molecules that are protective against ischemic brain injury owing to their participation in the regulation of vascular tone and cerebral blood flow. In addition, mEH metabolizes polycyclic aromatic hydrocarbons, one of the causative factors of atherosclerotic lesion development. In this study, we aimed to investigate the association of enzyme activity-modifying missense single nucleotide polymorphisms (SNPs) of the sEH gene ( EPHX2 ) and mEH gene ( EPHX1 ) and ischemic stroke risk in a Turkish population. Patients and Methods Genomic DNA of patients with large artery atherosclerotic ischemic stroke (n=237) and controls (n=120) was isolated from blood samples, and genotypes for Tyr113His (rs1051740) and His139Arg (rs2234922) SNPs of EPHX1 and Arg287Gln (rs751141) SNP of EPHX2 were attained by the PCR/RFLP method. Results Minor allele frequency and genotype distributions for Arg287Gln, Tyr113His and His139Arg SNPs did not differ significantly between stroke patients and controls. However, hypertension- and diabetes-associated ischemic stroke risk was decreased by EPHX1 and increased by EPHX2 variants in stratification analyses. Conclusion This study has shown for the first time that the polymorphic alleles of EPHX1 were unlikely to be associated with large artery atherosclerotic ischemic stroke susceptibility; however, protective effects were evident within subgroups of hypertension and diabetes. In addition, EPHX2 Arg287Gln polymorphism, which has been studied for the first time in a Turkish population, was not significantly related to ischemic stroke, but increased the stroke risk in subgroup analysis.

Soluble Epoxide Hydrolase as a Therapeutic Target for Neuropsychiatric Disorders

“…As for sEH, it catalyzes the metabolism of EETs, which exhibit potentially beneficial actions in stroke via vasodilation, neuroprotection, promotion of angiogenesis, suppression of platelet aggregation, oxidative stress, and post-ischemic inflammation [120]. In related research, hypertension-and diabetes-associated ischemic stroke risk increased through the EPHX2 gene variants in the Turkish population [121]. Moreover, serum oxylipin changes consistent with higher sEH activity played a key role in vascular cognitive impairment, which is associated with the injury of periventricular subcortical white matter [122].…”

Maternal pre-conceptional glyphosate exposure impacts the offspring hepatic and ovarian proteome

“…Soluble cytosolic EPHX2 ( Sandberg and Meijer, 1996 ) was reduced by GLY exposure in this study, suggesting that GLY has potential to interfere with chemical biotransformation or that EPHX2 is being depleted as part of an ovarian biotransformation response. EPHX2 is a member of a family of enzymes that convert epoxide substrates to diol metabolites, and increased activity of EPHX2 and other EPHX isoforms has been implicated in several disease pathologies ( Can Demirdöğen et al , 2020 ; Igawa et al , 2009 ; Lee et al , 2019 ; Rajapaksa et al , 2007 ).…”

Soluble Epoxide Hydrolase and Diabetes Complications

“…The rs751141 polymorphism of the Ephx2 gene has been associated with increased risk of ischemic stroke in individuals with [ 63 ] and without T2DM even after adjusting for covariates such as CYP metabolite concentrations. [ 64 ] The rs751141 polymorphism was more common in individuals with early neurological deterioration (END) in ischemic stroke compared to stroke without END [ 65 ] and was associated with lower plasma EpETrE concentrations.…”