Research Article| Volume 22, ISSUE 5, P417-425, May 2012

Download started.


Association between the rs1050450 glutathione peroxidase-1 (C > T) gene variant and peripheral neuropathy in two independent samples of subjects with diabetes mellitus

Published:December 27, 2010DOI:


      Glutathione peroxidase-1 (GPx-1) is an endogenous anti-oxidant enzyme. The T allele of the GPx-1 rs1050450 (C > T) gene variant is associated with reduced enzyme activity. Our aim was to examine the association between this gene variant and peripheral neuropathy in two cross-sectional samples of subjects with diabetes: (i) 773 Caucasian subjects were genotyped from the UCL Diabetes and Cardiovascular disease Study (UDACS) and (ii) 382 Caucasian subjects from the Ealing Diabetes Study (EDS). Peripheral neuropathy status (and oxidised-LDL [Ox-LDL:LDL] and plasma Total Ant-ioxidant Status [TAOS] in UDACS), were analysed in relation to genotype. We observed that: (i) In UDACS, the odds ratio (OR) for peripheral neuropathy in the T allele carriers compared to the CC genotype was 1.61 [1.10–2.28], p = 0.01. This remained significant after adjustment for other risk factors. Ox-LDL:LDL ratio was significantly elevated in T allele carriers (CC vs. CT/TT: 16.3 ± 2.4 v 18.0 ± 2.9 U/mmol LDL, p = 0.02). (ii) In EDS, the OR for peripheral neuropathy in the T allele carriers compared to the CC genotype was 1.95 [1.11–3.42], p = 0.02. This remained significant after adjustment for other risk factors. In conclusion, we observed a significant association between the T allele and peripheral neuropathy and LDL oxidation. This is the first paper to examine the rs1050450 variant in two samples of Caucasian subjects with diabetes. Prospective analysis of the gene variant is required in diabetic and healthy cohorts with measured plasma markers of oxidative stress to investigate the described association further.


      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 Nutrition, Metabolism and Cardiovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Thomas P.K.
        Diabetic peripheral neuropathies: their cost to patient and society and the value of knowledge of risk factors for development of interventions.
        Eur Neurol. 1999; 1: 35-43
        • Boulton A.J.
        • Gries F.A.
        • Jervell J.A.
        Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy.
        Diabet Med. 1998; 15: 508-514
        • Group TDCaCTR
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
        N Engl J Med. 1993; 329: 977-986
        • Bedlack R.S.
        • Edelman D.
        • Gibbs 3rd, J.W.
        • Kelling D.
        • Strittmatter W.
        • Saunders A.M.
        • et al.
        APOE genotype is a risk factor for neuropathy severity in diabetic patients.
        Neurology. 2003; 60: 1022-1024
        • Stephens J.W.
        • Gable D.R.
        • Hurel S.J.
        • Miller G.J.
        • Cooper J.A.
        • Humphries S.E.
        Increased plasma markers of oxidative stress are associated with coronary heart disease in males with diabetes mellitus and with 10-year risk in a prospective sample of males.
        Clin Chem. 2006; 52: 446-452
        • Kopprasch S.
        • Pietzsch J.
        • Kuhlisch E.
        • Fuecker K.
        • Temelkova-Kurktschiev T.
        • Hanefeld M.
        • et al.
        In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance.
        Diabetes. 2002; 51: 3102-3106
        • Beckett G.J.
        • Arthur J.R.
        Selenium and endocrine systems.
        J Endocrinol. 2005; 184: 455-465
        • Forgione M.A.
        • Weiss N.
        • Heydrick S.
        • Cap A.
        • Klings E.S.
        • Bierl C.
        • et al.
        Cellular glutathione peroxidase deficiency and endothelial dysfunction.
        Am J Physiol Heart Circ Physiol. 2002; 282: H1255-H1261
        • Espinola-Klein C.
        • Rupprecht H.J.
        • Bickel C.
        • Schnabel R.
        • Genth-Zotz S.
        • Torzewski M.
        • et al.
        Glutathione peroxidase-1 activity, atherosclerotic burden, and cardiovascular prognosis.
        Am J Cardiol. 2007; 99: 808-812
        • Blankenberg S.
        • Rupprecht H.J.
        • Bickel C.
        • Torzewski M.
        • Hafner G.
        • Tiret L.
        • et al.
        Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease.
        N Engl J Med. 2003; 349: 1605-1613
        • Sun D.Q.
        • Li A.W.
        • Li J.
        • Li D.G.
        • Li Y.X.
        • Hao F.
        • et al.
        Changes of lipid peroxidation in carbon disulfide-treated rat nerve tissues and serum.
        Chem Biol Interact. 2009; 179: 110-117
        • Kishi Y.
        • Nickander K.K.
        • Schmelzer J.D.
        • Low P.A.
        Gene expression of antioxidant enzymes in experimental diabetic neuropathy.
        J Peripher Nerv Syst. 2000; 5: 11-18
        • Martinez-Blasco A.
        • Bosch-Morell F.
        • Trenor C.
        • Romero F.J.
        Experimental diabetic neuropathy: role of oxidative stress and mechanisms involved.
        Biofactors. 1998; 8: 41-43
        • Rosenblat M.
        • Aviram M.
        Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies.
        Free Radic Biol Med. 1998; 24: 305-317
        • Guo Z.
        • Van Remmen H.
        • Yang H.
        • Chen X.
        • Mele J.
        • Vijg J.
        • et al.
        Changes in expression of antioxidant enzymes affect cell-mediated LDL oxidation and oxidized LDL-induced apoptosis in mouse aortic cells.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1131-1138
        • Ravn-Haren G.
        • Olsen A.
        • Tjonneland A.
        • Dragsted L.O.
        • Nexo B.A.
        • Wallin H.
        • et al.
        Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study.
        Carcinogenesis. 2006; 27: 820-825
        • Hamanishi T.
        • Furuta H.
        • Kato H.
        • Doi A.
        • Tamai M.
        • Shimomura H.
        • et al.
        Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases in Japanese type 2 diabetic patients.
        Diabetes. 2004; 53: 2455-2460
        • Tang N.P.
        • Wang L.S.
        • Yang L.
        • Gu H.J.
        • Sun Q.M.
        • Cong R.H.
        • et al.
        Genetic variant in glutathione peroxidase 1 gene is associated with an increased risk of coronary artery disease in a Chinese population.
        Clin Chim Acta. 2008; 395: 89-93
        • Kuzuya M.
        • Ando F.
        • Iguchi A.
        • Shimokata H.
        Glutathione peroxidase 1 Pro198Leu variant contributes to the metabolic syndrome in men in a large Japanese cohort.
        Am J Clin Nutr. 2008; 87: 1939-1944
        • Mir O.
        • Alexandre J.
        • Tran A.
        • Durand J.P.
        • Pons G.
        • Treluyer J.M.
        • et al.
        Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity.
        Ann Oncol. 2009; 20: 736-740
        • Chistiakov D.A.
        • Zotova E.V.
        • Savost’anov K.V.
        • Bursa T.R.
        • Galeev I.V.
        • Strokov I.A.
        • et al.
        The 262T > C promoter polymorphism of the catalase gene is associated with diabetic neuropathy in type 1 diabetic Russian patients.
        Diabete Metab. 2006; 32: 63-68
        • Dhamrait S.S.
        • Stephens J.W.
        • Cooper J.A.
        • Acharya J.
        • Mani A.R.
        • Moore K.
        • et al.
        Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2.
        Eur Heart J. 2004; 25: 468-475
        • Stephens J.W.
        • Dhamrait S.S.
        • Acharya J.
        • Humphries S.E.
        • Hurel S.J.
        A common variant in the ACE gene is associated with peripheral neuropathy in women with type 2 diabetes mellitus.
        J Diabet Complications. 2006; 20: 317-321
        • Alberti K.G.
        • Zimmet P.Z.
        New diagnostic criteria and classification of diabetes – again?.
        Diabet Med. 1998; 15: 535-536
        • American Diabetes Association
        • Neurology AAo
        Report and recommendations of the San Antonio conference on diabetic neuropathy.
        Diabetes Care. 1998; 11: 592-597
        • Sampson M.J.
        • Gopaul N.
        • Davies I.R.
        • Hughes D.A.
        • Carrier M.J.
        Plasma F2 isoprostanes: direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes.
        Diabetes Care. 2002; 25: 537-541
        • Scheffer P.G.
        • Bos G.
        • Volwater H.G.
        • Dekker J.M.
        • Heine R.J.
        • Teerlink T.
        Associations of LDL size with in vitro oxidizability and plasma levels of in vivo oxidized LDL in Type 2 diabetic patients.
        Diabet Med. 2003; 20: 563-567
        • Rothman K.J.
        No adjustments are needed for multiple comparisons.
        Epidemiology. 1990; 1: 43-46
        • Raaschou-Nielsen O.
        • Sorensen M.
        • Hansen R.D.
        • Frederiksen K.
        • Tjonneland A.
        • Overvad K.
        • et al.
        GPX1 Pro198Leu polymorphism, interactions with smoking and alcohol consumption, and risk for lung cancer.
        Cancer Lett. 2007; 247: 293-300
        • Steinbrecher U.P.
        • Parthasarathy S.
        • Leake D.S.
        • Witztum J.L.
        • Steinberg D.
        Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids.
        Proc Natl Acad Sci U S A. 1984; 81: 3883-3887
        • Said G.
        • Lacroix C.
        • Lozeron P.
        • Ropert A.
        • Plante V.
        • Adams D.
        Inflammatory vasculopathy in multifocal diabetic neuropathy.
        Brain. 2003; 126: 376-385
        • Tsuzura S.
        • Ikeda Y.
        • Suehiro T.
        • Ota K.
        • Osaki F.
        • Arii K.
        • et al.
        Correlation of plasma oxidized low-density lipoprotein levels to vascular complications and human serum paraoxonase in patients with type 2 diabetes.
        Metabolism. 2004; 53: 297-302
        • Sobal G.
        • Menzel J.E.
        • Sinzinger H.
        Influence of acetylsalicylic acid on oxidation of native and glycated low-density lipoprotein.
        Life Sci. 2000; 66: 1987-1998
        • Galland F.
        • Duvillard L.
        • Petit J.M.
        • Lagrost L.
        • Vaillant G.
        • Brun J.M.
        • et al.
        Effect of insulin treatment on plasma oxidized LDL/LDL-cholesterol ratio in type 2 diabetic patients.
        Diabete Metab. 2006; 32: 625-631
        • Risch N.J.
        Searching for genetic determinants in the new millennium.
        Nature. 2000; 405: 847-856