Accumulation of gene polymorphisms related to oxidative stress is associated with myocardial infarction in Japanese type 2 diabetic patients



      It is believed that oxidative stress, which is provoked in patients with diabetes, plays critical roles in the pathogenesis of myocardial infarction (MI). We simultaneously determined 5 relatively common genetic variants related to oxidative stress and evaluated the combined effect on MI.


      We enrolled 3819 Japanese type 2 diabetic subjects (males 60.8%, 60.6 ± 10.0 years old) and determined their genotypes regarding glutamate-cysteine ligase modifier subunit (GCLM) C-588T, manganese superoxide dismutase (SOD2) Val16Ala, endothelial nitric oxide synthase (NOS3) G894T, NAD(P)H oxidase p22phox (CYBA) C242T, and myeloperoxidase (MPO) G-463A polymorphisms. The diagnosis of the occurrence of MI was based on the clinical records, characteristic ECG changes, and the findings in coronary angiography and echocardiography.


      The single association analysis revealed that there were no statistically significant associations between each polymorphism and the prevalence of MI. Interestingly, the prevalence of MI was higher with the increase of the total number of 5 concomitant unfavorable “pro-oxidant alleles” in each subject (p value for linear trend = 0.018). Furthermore, a multiple logistic regression analysis showed that the number of pro-oxidant alleles was a risk factor for MI independently of conventional risk factors (odds ratio for 1-point increase in the number of pro-oxidant allele = 1.16 with 95% CI 1.01–1.34, p = 0.034).


      Accumulation of gene polymorphisms related to oxidative stress is likely associated with the prevalence of MI in type 2 diabetic patients, suggesting that the combined information about these variants is useful to assess the risk of MI.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • West I.C.
        Radicals in oxidative stress in diabetes.
        Diabet Med. 2002; 17: 171-180
        • Meister A.
        • Anderson M.E.
        Annu Rev Biochem. 1983; 52: 711-760
        • Minova H.R.
        • Mulcahy R.T.
        An electrophile responsive element (EpRE) regulates gamma-naphthoflavone induction of the human gamma-glutamylcysteine synthetase regulatory subunit gene.
        J Biol Chem. 1998; 273: 14683-14689
        • Nakamura S.
        • Kugiyama K.
        • Sugiyama S.
        • et al.
        Polymorphism in the 5′-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction.
        Circulation. 2002; 105: 2968-2973
        • Lebovitz R.M.
        • Zhang H.
        • Vogel H.
        • et al.
        Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice.
        Proc Natl Acad Sci USA. 1996; 93: 9782-9787
        • Shimoda-Matsubayashi S.
        • Matsumine H.
        • Kobayashi T.
        • Nakagawa-Hattori Y.
        • Shimizu Y.
        • Mizuno Y.
        Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease.
        Biochem Biophys Res Commun. 1996; 226: 561-565
        • Sutton A.
        • Khoury H.
        • Prip-Buus C.
        • Cepanec C.
        • Pessayre D.
        • Degoul F.
        The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.
        Pharmacogenetics. 2003; 13: 145-157
        • Shimoda-Matsubayashi S.
        • Hattori T.
        • Matsumine H.
        • et al.
        MnSOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson’ disease and control.
        Neurology. 1997; 49: 1257-1262
        • Tesauro M.
        • Thompson W.C.
        • Rogliani P.
        • Qi L.
        • Chaudhary P.P.
        • Moss J.
        Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298.
        Proc Natl Acad Sci USA. 2000; 97: 2832-2835
        • Wang X.L.
        • Sim A.S.
        • Wang M.X.
        • Murrell G.A.
        • Trudinger B.
        • Wang J.
        Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity.
        FEBS Lett. 2000; 471: 45-50
        • Veldman B.A.
        • Spiering W.
        • Doevendans P.A.
        • et al.
        The Glu298Asp polymorphism of the NOS3 gene as a determinant of the baseline production of nitric oxide.
        J Hypertens. 2002; 20: 2023-2027
        • Noiri E.
        • Satoh H.
        • Taguchi J.
        • et al.
        Association of eNOS Glu298Asp polymorphism with end-stage renal disease.
        Hypertension. 2002; 40: 535-540
        • Azumi H.
        • Inoue N.
        • Takeshita S.
        • et al.
        Expression of NADH/NADPH oxidase p22phox in human coronary arteries.
        Circulation. 1999; 100: 1494-1498
        • Guzik T.J.
        • West N.E.
        • Black E.
        • et al.
        Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis.
        Circulation. 2000; 102: 1744-1747
        • Daugherty A.
        • Dunn J.L.
        • Rateri D.L.
        • Heinecke J.W.
        Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.
        J Clin Invest. 1994; 94: 437-444
        • Reynolds W.F.
        • Chang E.
        • Douer E.
        • Ball E.D.
        • Kanda V.
        An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukaemia.
        Blood. 1997; 90: 2730-2737
        • Aviram M.
        • Hardak E.
        • Vaya J.
        • et al.
        Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities.
        Circulation. 2000; 101: 2510-2517
        • Yamada Y.
        • Izawa H.
        • Ichihara S.
        • et al.
        Prediction of the risk of myocardial infarction from polymorphisms in candidate genes.
        N Engl J Med. 2002; 347: 1916-1923
        • Dupont W.P.
        • Plummer W.D.
        Power and sample size calculations: a review and computer program.
        Control Clin Trials. 1990; 11: 116-128
        • Keating B.J.
        • Tischfield S.
        • Murray S.S.
        • et al.
        Concept, design and implementation of cardiovascular gene-centric 50K SNP array for large-scale genomic association studies.
        PLoS one. 2008; 3: e3583
        • Yang Q.
        • Khoury M.J.
        • Botto L.
        • Friedman J.M.
        • Flanders W.D.
        Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes.
        Am J Hum Genet. 2003; 72: 636-649
        • Cam S.F.
        • Sekuri C.
        • Tengiz I.
        • et al.
        The G894T polymorphism on endothelial nitric oxide synthase gene is associated with premature coronary artery disease in a Turkish population.
        Thromb Res. 2005; 116: 278-292
        • Tamemoto H.
        • Ishikawa S.E.
        • Kawakami M.
        Association of the Glu298Asp polymorphism of the eNOS gene with ischemic heart disease in Japanese diabetic subjects.
        Diabetes Res Clin Pract. 2008; 80: 275-279
        • Jaramillo P.C.
        • Munoz M.A.
        • Lanas M.C.
        • Lanas Z.F.
        • Salazar L.A.
        Endothelial nitric oxide synthase G894T gene polymorphism in Chilean subjects with coronary artery disease and controls.
        Clin Chim Acta. 2006; 371: 102-106
        • Inoue N.
        • Kawashima S.
        • Kanazawa K.
        • Yamada S.
        • Akita H.
        • Yokoyama M.
        Polymorphism of the NADH/NADPH oxidase p22phox gene in patients with coronary artery disease.
        Circulation. 1998; 97: 135-137
        • Soccio M.
        • Toniato E.
        • Evangelista V.
        • Carluccio M.
        • De Caterina R.
        Oxidative stress and cardiovascular risk: the role of vascular NAD(P)H oxidase and its genetic variants.
        Eur J Clin Invest. 2005; 35: 305-314
        • Nikpoor B.
        • Turecki G.
        • Fournier C.
        • Theroux P.
        • Rouleau G.A.
        A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians.
        Am Heart J. 2001; 142: 336-339
        • Makela R.
        • Loimaala A.
        • Nenonen A.
        • et al.
        The association of myeloperoxidase promoter polymorphism with carotid atherosclerosis is abolished in patients with type 2 diabetes.
        Clin Biochem. 2008; 41: 532-553
        • Wainstein R.V.
        • Wainstein M.V.
        • Riberio J.P.
        • et al.
        Association between myeloperoxidase polymorphisms and its plasma levels with severity of coronary artery disease.
        Clin Biochem. 2010; 43: 57-62
        • Fujimoto H.
        • Taguchi J.
        • Imai Y.
        • et al.
        Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease.
        Eur Heart J. 2008; 29: 1267-1274