ApoE polymorphisms and vascular damage in type 2 diabetics
Keywords:
APOLIPOPROTEIN E4, DIABETES MELLITUS TYPE 2, MYOCARDIAL ISCHEMIAAbstract
Introduction: apolipoproiten E (ApoE) is a constituent of plasma lipoproteins that plays an important role in metabolism acting as lipoprotein receptor ligand. Variations in the ApoE locus are associated to variations in concentration of low plasma density lipoproteins. Allele E4 has been associated to an increase of risk for cardiovascular disease, progress in diabetic nephropathies and severity and progression of diabetic neuropathies and retinopathies. Allele E2 is associated to conferring protection from coronary heart disease (CHD).
Objectives: to study the association between this polymorphism and the macroangiopathic effects, especially in terms of ischemic cardiopathy, and lipidogram in diabetic patients.
Method: 78 patients less than 85 years old with type 2 diabetes mellitus were studied, being the association between the ApoE polymorphism and the macroangiopathic and microangiopathic effects of diabetes assessed, as well as the lipidogram and age of patients at time of diagnosis. Genotype determination was done with standard extending-restricting methods following informed consent. Variables were analysed using Chi-scuared and the Fisher exact test. Alpha error rate was lower than 0.05.
Results: frequency of carriers of ApoE allele E4 among individuals with macroangiopathic complications was larger than among those who were free of these complications (26.2%), although differences were not statistically significant. The presence of ischemic heart disease was significantly associated with E4 allele that is 56% versus 25%. The presence of the E4 allele was significantly associated to the diagnosis of diabetes earlier than 40 years old. Patients with risk alleles evidenced increased values of LDL and triglycerides.
Conclusions: allele E4 was associated with a larger risk for ischemic cardiopathy and age of diagnosing type 2 diabetes mellitus lower than 40 years old. The strong effect of genotype ApoE was evidence on the lipid profile of patients with type 2 diabetes.
References
(1) Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, et al.The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int 2003; 63(4):1499-507.
(2) Berger M, Mönks D, Wanner C, Lindner TH. Diabetic nephropathy: an inherited disease or just a diabetic complication? Kidney Blood Press Res 2003; 26(3):143-54.
(3) Hansen T. Genetics of Type 2 Diabetes. Curr Sci 2002; 83(12):1477-82.
(4) Nabel EG. Cardiovascular disease. N Engl J Med 2003; 349(1):60-72.
(5) Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 2004; 110(13):1868-73.
(6) Nordfors L, Stenvinkel P, Marchlewska A, Weiss R, Heimbürger O, Bergström J, et al. Molecular genetics in renal medicine: what can we hope to achieve? Nephrol Dial Transplant 2002; 17(Suppl 3):5-11.
(7) Morbois-Trabut L, Chabrolle C, Garrigue MA, Lasfargues G, Lecomte P. Apolipoprotein E genotype and plasma lipid levels in Caucasian diabetic patients. Diabetes Metab 2006; 32(3):270-5.
(8) Martins IJ, Hone E, Foster JK, Sünram-Lea SI, Gnjec A, Fuller SJ, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 2006; 11(8):721-36.
(9) Contois JH, Anamani DE, Tsongalis GJ. The underlying molecular mechanism of apolipoprotein E polymorphism: relationships to lipid disorders, cardiovascular disease, and Alzheimer's disease. Clin Lab Med 1996; 16(1):105-23.
(10) Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation 2000; 101(12):1366-71.
(11) Saito M, Eto M, Nitta H, Kanda Y, Shigeto M, Nakayama K, et al. Effect of apolipoprotein E4 allele on plasma LDL cholesterol response to diet therapy in type 2 diabetic patients. Diabetes Care 2004; 27(6):1276-80.
(12) Donnelly LA, Palmer CN, Whitley AL, Lang CC, Doney AS, Morris AD, et al. Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study. Pharmacogenet Genomics 2008; 18(4):279-87.
(13) Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Arterioscler Thromb Vasc Biol 1996; 16(10):1250-5.
(14) Humphries SE, Talmud PJ, Hawe E, Bolla M, Day IN, Miller GJ. Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 2001; 358(9276):115-9.
(15) Vaisi-Raygani A, Rahimi Z, Nomani H, Tavilani H, Pourmotabbed T. The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. Clin Biochem 2007; 40(15):1150-6.
(16) Santos A, Salguero ML, Gurrola C, Muñoz F, Roig-Melo E, Panduro A. The epsilon4 allele of apolipoprotein E gene is a potential risk factor for the severity of macular edema in type 2 diabetic Mexican patients. Ophthalmic Genet 2002; 23(1):13-9.
(17) Joss N, Jardine A, Gaffney D, Boulton-Jones JM. Influence of apolipoprotein E genotype on progression of diabetic nephropathy. Nephron Exp Nephrol 2005; 101(4):e127-33.
(18) Leiva E, Mujica V, Elematore I, Orrego R, Díaz G, Prieto M, et al. Relationship between Apolipoprotein E polymorphism and nephropathy in type-2 diabetic patients. Diabetes Res Clin Pract 2007; 78(2):196-201.
(19) Guan J, Zhao HL, Baum L, Sui Y, He L, Wong H, et al. Apolipoprotein E polymorphism and expression in type 2 diabetic patients with nephropathy: clinicopathological correlation. Nephrol Dial Transplant 2009; 24(6):1889-95.
(20) Carmena R, Masana L, Rubiés J. Alteraciones del Metabolismo de las Lipoproteínas. In: Farreras Valentí P, Rozman C. Medicina Interna. 15 ed. Madrid: Elsevier, 2004; 15:1914-35.
(21) Rea IM, Mc Dowell I, McMaster D, Smye M, Stout R, Evans A; MONICA group (Belfast). Monitoring of Cardiovascular trends study group. Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-living Ageing Study (BELFAST). Mech Ageing Dev 2001; 122(13):1367-72.
(22) Zivelin A, Rosenberg N, Peretz H, Amit Y, Kornbrot N, Seligsohn U. Improved method for genotyping apolipoprotein E polymorphisms by a PCR-based assay simultaneously utilizing two distinct restriction enzymes. Clin Chem 1997; 43(9):1657-9.
(23) Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med 2002; 4(2):45-61.
(24) Guang-da X, You-ying L, Zhi-song C, Yu-sheng H, Xiang-jiu Y. Apolipoprotein e4 allele is predictor of coronary artery disease death in elderly patients with type 2 diabetes mellitus. Atherosclerosis 2004; 175(1):77-81.
(25) Vaisi-Raygani A, Rahimi Z, Nomani H, Tavilani H, Pourmotabbed T. The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. Clin Biochem 2007; 40(15):1150-6.
(26) Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002; 155(6):487-95.
(27) Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation 2000; 101(12):1366-71.
(28) Saito M, Eto M, Nitta H, Kanda Y, Shigeto M, Nakayama K, et al. Effect of apolipoprotein E4 allele on plasma LDL cholesterol response to diet therapy in type 2 diabetic patients. Diabetes Care 2004; 27(6):1276-80.
(29) Chaudhary R, Likidlilid A, Peerapatdit T, Tresukosol D, Srisuma S, Ratanamaneechat S, et al. Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. Cardiovasc Diabetol 2012; 11:36.
(30) Eto M, Watanabe K, Iwashima Y, Morikawa A, Chonan N, Oshima E, et al. Increased frequency of apolipoprotein epsilon 4 allele in type II diabetes with hypercholesterolemia. Diabetes 1987; 36(11):1301-6.
(31) Oh JY, Barrett-Connor E; Rancho Bernardo Study Group. Apolipoprotein E polymorphism and lipid levels differ by gender and family history of diabetes: the Rancho Bernardo Study. Clin Genet 2001; 60(2):132-7.
(32) Kalina A, Szalai C, Prohászka Z, Reiber I, Császár A. Association of plasma lipid levels with apolipoprotein E polymorphism in Type 2 diabetes. Diabetes Res Clin Pract 2002; 56(1):63-8.
(33) Jiang R, Schulze MB, Li T, Rifai N, Stampfer MJ, Rimm EB, et al. Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. Diabetes Care 2004; 27(8):1991-7.
(34) Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 2004; 110(13):1868-73.
(35) Musunuru K, Kathiresan S. Genetics of coronary artery disease. Annu Rev Genomics Hum Genet 2010; 11:91-108.
(36) Dandona S, Stewart AF, Roberts R. Genomics in coronary artery disease: past, present and future. Can J Cardiol 2010; 26(Suppl A):56A-59A.
(37) Groop L, Lyssenko V. Genetics of type 2 diabetes: an overview. Endocrinol Nutr 2009; 56(Suppl 4):34-7.
(38) Stoll M, Esperón P, Raggio V, Lorenzo M, Artucio MC, Kuster F. Combination of genetic polymorphisms and smoker status in high risk families. Poster Presentations. En: The 16th 2008 World Congress of Cardiology; 2008 May 18 - 21; Buenos Aires, Argentina.
(39) O'Donnell CJ, Nabel EG. Genomics of cardiovascular disease. N Engl J Med 2011; 365(22):2098-109.
(40) Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007; 316(5830):1491-3.
(41) Kennon B, Petrie JR, Small M, Connell JM. Angiotensin-converting enzyme gene and diabetes mellitus. Diabet Med 1999; 16(6):448-58.
(42) Siffert W. G protein beta 3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy. Nephrol Dial Transplant 2000; 15(9):1298-306.
(43) Levy AP, Hochberg I, Jablonski K, Resnick HE, Lee ET, Best L, et al. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol 2002; 40(11):1984-90.
(44) Levy AP, Roguin A, Hochberg I, Herer P, Marsh S, Nakhoul FM, et al. Haptoglobin phenotype and vascular complications in patients with diabetes. N Engl J Med 2000; 343(13):969-70.
(45) Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996; 273(5281):1516-7.
(46) Lane RM, Farlow MR. Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. J Lipid Res 2005; 46(5):949-68.
(47) Hsiung GY, Sadovnick AD, Feldman H. Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging. CMAJ 2004; 171(8):863-7.
(48) Helbecque N, Amouyel P. Commonalities between genetics of cardio vascular disease and neurodegenerative disorders. Curr Opin Lipidol 2004; 15(2):121-7.
(49) Martins IJ, Hone E, Foster JK, Sünram-Lea SI, Gnjec A, Fuller SJ, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 2006; 11(8):721-36.
(2) Berger M, Mönks D, Wanner C, Lindner TH. Diabetic nephropathy: an inherited disease or just a diabetic complication? Kidney Blood Press Res 2003; 26(3):143-54.
(3) Hansen T. Genetics of Type 2 Diabetes. Curr Sci 2002; 83(12):1477-82.
(4) Nabel EG. Cardiovascular disease. N Engl J Med 2003; 349(1):60-72.
(5) Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 2004; 110(13):1868-73.
(6) Nordfors L, Stenvinkel P, Marchlewska A, Weiss R, Heimbürger O, Bergström J, et al. Molecular genetics in renal medicine: what can we hope to achieve? Nephrol Dial Transplant 2002; 17(Suppl 3):5-11.
(7) Morbois-Trabut L, Chabrolle C, Garrigue MA, Lasfargues G, Lecomte P. Apolipoprotein E genotype and plasma lipid levels in Caucasian diabetic patients. Diabetes Metab 2006; 32(3):270-5.
(8) Martins IJ, Hone E, Foster JK, Sünram-Lea SI, Gnjec A, Fuller SJ, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 2006; 11(8):721-36.
(9) Contois JH, Anamani DE, Tsongalis GJ. The underlying molecular mechanism of apolipoprotein E polymorphism: relationships to lipid disorders, cardiovascular disease, and Alzheimer's disease. Clin Lab Med 1996; 16(1):105-23.
(10) Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation 2000; 101(12):1366-71.
(11) Saito M, Eto M, Nitta H, Kanda Y, Shigeto M, Nakayama K, et al. Effect of apolipoprotein E4 allele on plasma LDL cholesterol response to diet therapy in type 2 diabetic patients. Diabetes Care 2004; 27(6):1276-80.
(12) Donnelly LA, Palmer CN, Whitley AL, Lang CC, Doney AS, Morris AD, et al. Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study. Pharmacogenet Genomics 2008; 18(4):279-87.
(13) Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Arterioscler Thromb Vasc Biol 1996; 16(10):1250-5.
(14) Humphries SE, Talmud PJ, Hawe E, Bolla M, Day IN, Miller GJ. Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 2001; 358(9276):115-9.
(15) Vaisi-Raygani A, Rahimi Z, Nomani H, Tavilani H, Pourmotabbed T. The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. Clin Biochem 2007; 40(15):1150-6.
(16) Santos A, Salguero ML, Gurrola C, Muñoz F, Roig-Melo E, Panduro A. The epsilon4 allele of apolipoprotein E gene is a potential risk factor for the severity of macular edema in type 2 diabetic Mexican patients. Ophthalmic Genet 2002; 23(1):13-9.
(17) Joss N, Jardine A, Gaffney D, Boulton-Jones JM. Influence of apolipoprotein E genotype on progression of diabetic nephropathy. Nephron Exp Nephrol 2005; 101(4):e127-33.
(18) Leiva E, Mujica V, Elematore I, Orrego R, Díaz G, Prieto M, et al. Relationship between Apolipoprotein E polymorphism and nephropathy in type-2 diabetic patients. Diabetes Res Clin Pract 2007; 78(2):196-201.
(19) Guan J, Zhao HL, Baum L, Sui Y, He L, Wong H, et al. Apolipoprotein E polymorphism and expression in type 2 diabetic patients with nephropathy: clinicopathological correlation. Nephrol Dial Transplant 2009; 24(6):1889-95.
(20) Carmena R, Masana L, Rubiés J. Alteraciones del Metabolismo de las Lipoproteínas. In: Farreras Valentí P, Rozman C. Medicina Interna. 15 ed. Madrid: Elsevier, 2004; 15:1914-35.
(21) Rea IM, Mc Dowell I, McMaster D, Smye M, Stout R, Evans A; MONICA group (Belfast). Monitoring of Cardiovascular trends study group. Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-living Ageing Study (BELFAST). Mech Ageing Dev 2001; 122(13):1367-72.
(22) Zivelin A, Rosenberg N, Peretz H, Amit Y, Kornbrot N, Seligsohn U. Improved method for genotyping apolipoprotein E polymorphisms by a PCR-based assay simultaneously utilizing two distinct restriction enzymes. Clin Chem 1997; 43(9):1657-9.
(23) Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med 2002; 4(2):45-61.
(24) Guang-da X, You-ying L, Zhi-song C, Yu-sheng H, Xiang-jiu Y. Apolipoprotein e4 allele is predictor of coronary artery disease death in elderly patients with type 2 diabetes mellitus. Atherosclerosis 2004; 175(1):77-81.
(25) Vaisi-Raygani A, Rahimi Z, Nomani H, Tavilani H, Pourmotabbed T. The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. Clin Biochem 2007; 40(15):1150-6.
(26) Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002; 155(6):487-95.
(27) Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation 2000; 101(12):1366-71.
(28) Saito M, Eto M, Nitta H, Kanda Y, Shigeto M, Nakayama K, et al. Effect of apolipoprotein E4 allele on plasma LDL cholesterol response to diet therapy in type 2 diabetic patients. Diabetes Care 2004; 27(6):1276-80.
(29) Chaudhary R, Likidlilid A, Peerapatdit T, Tresukosol D, Srisuma S, Ratanamaneechat S, et al. Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. Cardiovasc Diabetol 2012; 11:36.
(30) Eto M, Watanabe K, Iwashima Y, Morikawa A, Chonan N, Oshima E, et al. Increased frequency of apolipoprotein epsilon 4 allele in type II diabetes with hypercholesterolemia. Diabetes 1987; 36(11):1301-6.
(31) Oh JY, Barrett-Connor E; Rancho Bernardo Study Group. Apolipoprotein E polymorphism and lipid levels differ by gender and family history of diabetes: the Rancho Bernardo Study. Clin Genet 2001; 60(2):132-7.
(32) Kalina A, Szalai C, Prohászka Z, Reiber I, Császár A. Association of plasma lipid levels with apolipoprotein E polymorphism in Type 2 diabetes. Diabetes Res Clin Pract 2002; 56(1):63-8.
(33) Jiang R, Schulze MB, Li T, Rifai N, Stampfer MJ, Rimm EB, et al. Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. Diabetes Care 2004; 27(8):1991-7.
(34) Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 2004; 110(13):1868-73.
(35) Musunuru K, Kathiresan S. Genetics of coronary artery disease. Annu Rev Genomics Hum Genet 2010; 11:91-108.
(36) Dandona S, Stewart AF, Roberts R. Genomics in coronary artery disease: past, present and future. Can J Cardiol 2010; 26(Suppl A):56A-59A.
(37) Groop L, Lyssenko V. Genetics of type 2 diabetes: an overview. Endocrinol Nutr 2009; 56(Suppl 4):34-7.
(38) Stoll M, Esperón P, Raggio V, Lorenzo M, Artucio MC, Kuster F. Combination of genetic polymorphisms and smoker status in high risk families. Poster Presentations. En: The 16th 2008 World Congress of Cardiology; 2008 May 18 - 21; Buenos Aires, Argentina.
(39) O'Donnell CJ, Nabel EG. Genomics of cardiovascular disease. N Engl J Med 2011; 365(22):2098-109.
(40) Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007; 316(5830):1491-3.
(41) Kennon B, Petrie JR, Small M, Connell JM. Angiotensin-converting enzyme gene and diabetes mellitus. Diabet Med 1999; 16(6):448-58.
(42) Siffert W. G protein beta 3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy. Nephrol Dial Transplant 2000; 15(9):1298-306.
(43) Levy AP, Hochberg I, Jablonski K, Resnick HE, Lee ET, Best L, et al. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol 2002; 40(11):1984-90.
(44) Levy AP, Roguin A, Hochberg I, Herer P, Marsh S, Nakhoul FM, et al. Haptoglobin phenotype and vascular complications in patients with diabetes. N Engl J Med 2000; 343(13):969-70.
(45) Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996; 273(5281):1516-7.
(46) Lane RM, Farlow MR. Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. J Lipid Res 2005; 46(5):949-68.
(47) Hsiung GY, Sadovnick AD, Feldman H. Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging. CMAJ 2004; 171(8):863-7.
(48) Helbecque N, Amouyel P. Commonalities between genetics of cardio vascular disease and neurodegenerative disorders. Curr Opin Lipidol 2004; 15(2):121-7.
(49) Martins IJ, Hone E, Foster JK, Sünram-Lea SI, Gnjec A, Fuller SJ, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 2006; 11(8):721-36.
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2013-09-30
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Guerra A, Raggio V, Esperón P, Fraga L, Valiño J, Pisano Sánchez A, et al. ApoE polymorphisms and vascular damage in type 2 diabetics. Rev. Méd. Urug. [Internet]. 2013 Sep. 30 [cited 2024 Nov. 23];29(3):137-46. Available from: https://revista.rmu.org.uy/index.php/rmu/article/view/273
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