CYP Genetic Variants, CYP Metabolite Levels, and Symptomatic Carotid Stenosis in Ischemic Stroke Patients

Aim: To evaluate the relationship between CYP genetic polymorphisms and CYP metabolite levels with carotid artery stenosis in acute ischemic stroke (IS) patients. Methods: Eleven single nucleotide polymorphisms (SNPs) of seven CYP genes were genotyped in 136 IS patients with carotid stenosis and 158 patients without carotid stenosis. CYP plasma metabolite levels [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] were assessed in a subsample of 90 patients with carotid stenosis and 96 patients without carotid stenosis. We evaluated the relationship between assessed variants and carotid stenosis risk, variants with CYP metabolite levels, and variants in mediating the differences of CYP metabolite levels between patients with carotid stenosis and those without. Additionally, gene-gene interactions were analyzed to assess the interactive role of the assessed variants in affecting CYP metabolite levels and risk of carotid stenosis. Results: The genotypes of rs17110453CC, rs751141GG, and rs9333025GG were significantly associated with carotid stenosis risk. Also these polymorphisms were associated with CYP plasma metabolite levels in patients with carotid stenosis. There was a significant gene-gene interaction between rs17110453 and rs9333025 in affecting the risk of carotid stenosis. Patients with rs17110453CC and rs9333025GG had a significantly higher risk of carotid stenosis than those with 17110453AA and rs9333025AA (OR=2.12, 95% CI: 1.13-7.26, P = 0.013). Conclusions: Specific CYP450 gene SNPs and their interactions are associated with CYP450 plasma metabolite levels, which may partially explain their associations with carotid stenosis. Further studies are needed to validate our findings.