Polimorfismos de ApoE y daño vascular en diabéticos tipo 2
Palabras clave:
APOLIPOPROTEÍNA E4, DIABETES MELLITUS TIPO 2, ISQUEMIA MIOCARDICA
Resumen
Introducción: la apolipoproteína E (ApoE) es un constituyente de las lipoproteínas plasmáticas con un importante rol en el metabolismo como ligando de receptores de lipoproteínas. Las variaciones en el locus de ApoE se vinculan a variaciones en las concentraciones de lipoproteínas de baja densidad (LDL) plasmáticas. El alelo E4 se ha vinculado a aumento del riesgo cardiovascular, a progresión de la nefropatía diabética así como a severidad y progresión de neuropatía y retinopatía diabéticas. El alelo E2 se asocia a un efecto final protector para el desarrollo de enfermedad cardiovascular.
Objetivos: estudiar la asociación entre este polimorfismo y las repercusiones macroangiopáticas, en especial cardiopatía isquémica, y el lipidograma en los pacientes diabéticos.
Material y método: se estudiaron 78 pacientes diabéticos tipo 2, menores de 85 años de edad, valorando la asociación entre el polimorfismo de ApoE y las repercusiones macroangiopáticas y microangiopáticas de la diabetes, el lipidograma y la edad al diagnóstico de la diabetes. La determinación genotípica se realizó por métodos estándar de amplificación-restricción previo consentimiento informado. Las variables se analizaron utilizando chi cuadrado y prueba de Fisher. Error alfa menor a 0,05.
Resultados: la frecuencia de portadores del alelo E4 de la Apo E entre los individuos con complicaciones macroangiopáticas (43,5%) fue mayor que entre los que estaban libres de estas complicaciones (26,2%), si bien las diferencias no fueron estadísticamente significativas. La presencia de cardiopatía isquémica se asoció en forma significativa con el alelo E4, 56% versus 25%. La presencia del alelo E4 se asoció significativamente con un diagnóstico de diabetes antes de los 40 años. Los pacientes con alelos de riesgo presentaron valores de LDL y triglicéridos (TG) aumentados.
Conclusiones: el alelo E4 se asoció a un mayor riesgo de cardiopatía isquémica y una edad al diagnóstico de DM2 menor a 40 años. Se evidenció un efecto marcado del genotipo de ApoE sobre el perfil lipídico de los pacientes diabéticos tipo 2.
Citas
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(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.
Publicado
2013-09-30
Cómo citar
1.
Guerra A, Raggio V, Esperón P, Fraga L, Valiño J, Pisano Sánchez A, Pisano Rondeau A, Martínez R, Borgia F, Schwedt E, Belloso A, Stoll M. Polimorfismos de ApoE y daño vascular en diabéticos tipo 2. Rev. Méd. Urug. [Internet]. 30 de septiembre de 2013 [citado 24 de noviembre de 2024];29(3):137-46. Disponible en: http://www2.rmu.org.uy/ojsrmu311/index.php/rmu/article/view/273
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