Abstract
Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase stroke. Therefore, investigation of the polymorphisms of enzymes is of crucial importance to determine the molecular etiology of the disease. To test this hypothesis, we performed a case–control study in which we compared the distribution of CYP2E1 and NQO1 genotypes between 245 large artery atherosclerotic ischemic stroke patients and 145 controls, using PCR–RFLP. A significant difference was observed between stroke patients and controls with respect to the CYP2E1*5B genotype (odds ratio; OR 8.069, P = 0.011) and allele (OR 7.876, P = 0.011) distribution. However, this polymorphism was not a significant predictor of disease status in logistic regression analysis. NQO1*2 polymorphism genotype distribution was significantly different between patients and controls (P = 0.027) and heterozygote *1*2 genotype was found to be a protective factor against large artery atherosclerotic ischemic stroke in logistic regression analysis (OR 0.562, P = 0.018). This is the first study conducted regarding the association of CYP2E1 and NQO1 genetic polymorphisms and large artery atherosclerotic ischemic stroke risk in Turkish population.
Similar content being viewed by others
References
Nagai Y, Kitagawa K, Sakaguchi M et al (2001) Significance of earlier carotid atherosclerosis for stroke subtypes. Stroke 32:1780–1785
Antoniades C, Tousoulis D, Tentolouris C et al (2003) Oxidative stress, antioxidant vitamins, and atherosclerosis. From basic research to clinical practice. Herz 28:628–638
Crack PJ, Taylor JM (2005) Reactive oxygen species and the modulation of stroke. Free Radic Bio Med 38:1433–1444
Gonzalez FJ (1989) The molecular biology of cytochrome P450s. Pharmacol Rev 40:243–288
Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13:24–34
Aviram M, Kent UM, Hollenberg PF (1999) Microsomal cytochromes P450 catalyze the oxidation of low density lipoprotein. Atherosclerosis 143:253–260
Hayashi S, Watanabe J, Kawajiri K (1991) Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J Biochem 110(4):559–565
Uematsu F, Kikuchi H, Motomiya M et al (1991) Association between restriction fragment length polymorphism of the human cytochrome P4502E1 gene and susceptibility to lung cancer. Jpn J Cancer Res 82:254–256
Haufroid V, Buchet JP, Gardinal S et al (2002) Cytochrome P4502E1 phenotyping and the measurement of the chlorzoxazone metabolic ratio: assessment of its usefulness in workers exposed to styrene. Int Arch Occup Environ Health 75:453–458
Vodicak P, Soucek P, Tates AD et al (2001) Association between genetic polymorphisms and biomarkers in styrene-exposed workers. Mutat Res 482:89–103
Fairbrother A, Grove J, de Waziers I et al (1998) Detection and characterization of novel polymorphisms in the CYP2E1 gene. Pharmacogenetics 8:543–552
Wu X, Amos CI, Kemp BL et al (1998) Cytochrome P450 2E1 DraI polymorphism in lung cancer in minority populations. Cancer Epidem Biomark 7:13–18
Liu S, Park JY, Schantz SP et al (2001) Elucidation of CYP2E1 5′ regulatory RsaI/PstI allelic variants and their role in risk for oral cancer. Oral Oncol 37:437–445
Ulusoy G, Adali O, Boyunegmez Tumer T et al (2007) Significance of genetic polymorphisms at multiple loci of CYP2E1 in the risk of development of childhood acute lymphoblastic leukemia. Oncology 72:125–131
Salama SA, Au WW, Hunter GC et al (2002) Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers. Environ Mol Mutagen 40:153–160
Joseph P, Long DJ Jr, Klein-Szanto AJ et al (2000) Role of NAD(P)H:quinone oxidoreductase 1 (DT diaphorase) in protection against quinone toxicity. Biochem Pharmacol 60:207–214
Riley RJ, Workman P (1992) DT-diaphorase and cancer chemotherapy. Biochem Pharmacol 43:1657–1669
Siegel D, Gustafson DL, Dehn DL et al (2004) NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 65:1238–1247
Zhu H, Jia Z, Mahaney JE et al (2007) The highly expressed and inducible endogenous NAD(P)H:quinone oxidoreductase 1 in cardiovascular cells acts as a potential superoxide scavenger. Cardiovasc Toxicol 7:202–211
Ross D, Kepa JK, Winski SL et al (2000) NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129:77–97
Siegel D, McGuinness SM, Winski SL et al (1999) Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics 19:113–121
Kuehl BL, Paterson JW, Peacock JW et al (1995) Presence of 422 a heterozygous substitution and its relationship to DT-diaphorase activity. Cancer 72:555–561
Han SJ, Kang ES, Kim HJ et al (2009) The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes. Mol Genet Metab 97(1):85–90
Martin NJ, Collier AC, Bowen LD et al (2009) Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress. Mutat Res 674(1–2):93–100
Can Demirdöğen B, Şahin E, Türkanoğlu Özçelik A et al (2012) Apolipoprotein A5 polymorphisms in Turkish population: association with serum lipid profile and risk of ischemic stroke. Mol Biol Rep 39(12):10459–10468
Lahiri D, Schnabel B (1993) DNA Isolation by a rapid method from human blood samples: effects of MgCl2, EDTA, storage time, and temperature on DNA yield and quality. Biochem Genet 31(7–8):321–328
Yang BM, O’Reilly DA, Demaine AG et al (2001) Study of polymorphisms in the CYP2E1 gene in patients with alcoholic pancreatitis. Alcohol 23:91–97
Eguchi-Ishimae M, Eguchi M, Ishii E et al (2005) The association of a distinctive allele of NAD(P)H:quinone oxidoreductase with pediatric acute lymphoblastic leukemias with MLL fusion genes in Japan. Haematologica 90:1511–1515
Arınç E, Adalı O, İşcan M et al (1991) Stimulatory effects of benzene on rabbit liver and kidney microsomal cytochrome P-450 dependent drug metabolizing enzymes. Arch Toxicol 65:186–190
Gonzalez FJ (2005) Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res 569:101–110
Raunio H, Husgafvel-Pursiainen K, Anttila S et al (1995) Diagnosis of polymorphisms in carcinogen activating and inactivating enzymes and cancer susceptibility. Gene 159:113–121
Shyu HY, Fong CS, Fu YP et al (2010) Genotype polymorphisms of GGCX, NQO1, and VKORC1 genes associated with risk susceptibility in patients with large-artery atherosclerotic stroke. Clin Chim Acta 411:840–845
Ernster L, Lind C, Rase B (1972) A study of the DT-diaphorase activity of warfarin resistant rats. Eur J Biochem 25:198–206
Nioi P, Hayes JD (2004) Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic region leucine zipper and the arylhydrocarbon receptor basic helix–loop–helix transcription factors. Mutat Res 555:149–171
de Champlain J, Wu R, Girouard H et al (2004) Oxidative stress in hypertension. Clin Exp Hypertens 26:593–601
Lawes CM, Bennett DA, Feigin VL et al (2004) Blood pressure and stroke: an overview of published reviews. Stroke 35:776–785
Kumral E, Ozkaya B, Sagduyu A et al (1998) The Ege Stroke Registry: a hospital-based study in the Aegean region, Izmir, Turkey. Analysis of 2,000 stroke patients. Cerebrovasc Dis 8(5):278–288
Aviram M (1993) Modified forms of low density lipoprotein and atherosclerosis. Atherosclerosis 98:1–9
Wannamethee SG, Shaper AG, Ebrahim S (2000) HDL-cholesterol, total cholesterol, and the risk of stroke in middle-aged British men. Stroke 31:1882–1888
Tanne D, Koren-Morag N, Graff E et al (2001) Blood lipids and first-ever ischemic stroke/transient ischemic attack in the Bezafibrate Infarction Prevention (BIP) Registry high triglycerides constitute an independent risk factor. Circulation 104:2892–2897
Sever PS, Dahlöf B, Poulter NR et al (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 361:1149–1158
Cannon CP, Braunwald E, McCabe CH et al (2004) Pravastatin or Atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504
LaRosa JC, Grundy SM, Waters DD et al (2005) Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352:1425–1435
Baigent C, Blackwell L, Emberson J et al (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet 376:1670–1681
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interests.
Rights and permissions
About this article
Cite this article
Türkanoğlu Özçelik, A., Can Demirdöğen, B., Demirkaya, Ş. et al. Association of cytochrome P4502E1 and NAD(P)H:quinone oxidoreductase 1 genetic polymorphisms with susceptibility to large artery atherosclerotic ischemic stroke: a case–control study in the Turkish population. Neurol Sci 38, 1077–1085 (2017). https://doi.org/10.1007/s10072-017-2930-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-017-2930-9