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HMGCR and ApoE mutations may cause different responses to lipid lowering statin therapy
Corresponding Author(s) : D. Kirac
Cellular and Molecular Biology,
Vol. 63 No. 10: Issue 10
Abstract
Coronary artery disease (CAD) and its complications are the major causes of death in the world. Although statins have been used to lower lipid levels in CAD patients, this goal can not be attained in 1/3 of the patients. The objective of this study was to investigate whether common variations in HMG-CoA Reductase(HMGCR) and Apolipoprotein E (ApoE) genes involved in lipid and statin metabolism modify the effect of statins on serum lipid and lipoprotein concentrations in CAD patients.A hundred CAD patients were enrolled into the study. At the beginning of the study biochemical measurements were performed to determine the baseline levels performed. Patients were treated with 40 mg atorvastatin for 2 months and biochemical measurements were repeated. According to the post-treatment, LDL-c levels, patients were divided into 2 groups as non-responders and responders, respectively. The information regarding the risk factors such as smoking, alcohol consumption etc. were also obtained. DNA was isolated from peripheral blood. The presence of rs17244841 ve rs17238540 mutations in HMGCR and ε2, ε3 and ε4 variants of ApoE were determined by using RT-PCR. Results were evaluated statistically. HMGCR mutatations were mostly found in responders and ε4 variant of ApoE was mostly found in non-responders. It was also found that presence of HMGCR mutations causes a significant reduction in total cholesterol and LDL-c levels. Also presence of ε2 variant of ApoE causes a statistically significant increase in trigliseride levels. Our findings should be investigated with other researchers to clarify the mechanism.
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- Kajinami K, Akao H, Polisecki E, Schaefer J. Pharmacogenomics of statin responsiveness. Am J Cardiol 2005;96(9A):65-70.
- Peters BJ, Pett H, Klungel OH, Stricker BH, Psaty BM, Glazer NL, et al. Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI. Atherosclerosis 2011;217(2):458-64.
- Fiegenbaum M, da Silveira FR, Van der Sand CR, Van der Sand LC, Ferreira ME, Pires RC, et al. Pharmacogenetic study of apolipoprotein E, cholesteryl ester transfer protein and hepatic lipase genes and simvastatin therapy in Brazilian subjects. Clin Chim Acta 2005;362(1-2):182-8.
- Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J 2006;6(6):360-74.
- Postmus I, Verschuren JJ, de Craen AJ, Slagboom PE, Westendorp RG, Jukema JW, et al. Pharmacogenetics of statins: achievements, whole-genome analyses and future perspectives. Pharmacogenomics 2012;13(7):831-40.
- Voora D, Shah SH, Reed CR, Zhai J, Crosslin DR, Messer C, et al. Pharmacogenetic predictors of statin-mediated low-densitylipoprotein cholesterol reduction and dose response. Circ Cardiovasc Genet 2008;1(2):100-6.
- Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoproteincholesterol response to simvastatin treatment. Circulation 2008;117(12):1537-44.
- Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP Jr, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004;291:2821–27.
- Thompson JF, Man M, Johnson KJ, Wood LS, Lira ME, Lloyd DB, et al. An association study of 43 SNPs in 16 candidate genes with atorvastatin response. Pharmacogenomics J 2005;5:352–58.
- Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, Cox DR, et al. Comprehensive whole genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circ Cardiovasc Genet 2009;2(2):173-81.
- Christidis DS, Liberopoulos EN, Kakafika AI, Miltiadous GA, Cariolou M, Ganotakis ES, et al. The effect of apolipoprotein E polymorphism on the response to lipid-lowering treatment with atorvastatin or fenofibrate. J Cardiovasc Pharmacol Ther 2006;11(3):211-21.
- Saidi S, Slamia LB, Ammou SB, Mahjoub T, Almawi WY. Association of apolipoprotein E gene polymorphism with ischemicstroke involving large-vessel disease and its relation to serum lipidlevels. J Stroke Cerebrovasc Dis 2007;16(4):160-6.
- Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, et al. Genome-wide association study of genetic determinants of LDL-cresponse to atorvastatin therapy: importance of Lp(a). J Lipid Res 2012;53(5):1000-11.
- Yamauchi K, Tozuka M, Nakabayashi T, Sugano M, Hidaka H, Kondo Y, et al. Apolipoprotein E in cerebrospinal fluid: Relation to phenotype and plasma apolipoprotein E concentrations. Clin Chem 1999;45(4):497-504.
- Luc G, Bard JM, Arveiler D, Evans A, Cambou JP, Bingham A, et al. Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study. Arterioscl, Thromb Vas 1994;14:1412-19.
- Poduri A, Khullar M, Bahl A, Sehrawat BS, Sharma Y, Talwar KK. Common variants of HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy. DNA Cell Biol 2010;29(10):629-37.
- Polisecki E, Muallem H, Maeda N, Peter I, Robertson M, McMahon AD, et al. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Investigators. Genetic variation at the LDL receptor and HMG-CoA reductase geneloci, lipid levels, statin response, and cardiovascular diseaseincidence in PROSPER. Atherosclerosis 2008;200(1):109-14.
- Kajinami K, Takekoshi N, Brousseau ME, Schaefer EJ. Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. Atherosclerosis 2004;177(2):219-34.
- Lehtimaki T, Moilanen T, Nikkari T, Solakivi T, Porkka K, Ehnholm C, et al. Regional differences in apolipoprotein E polymorphism in Finland. Ann Med 1991;23(1), 61–66.
- Ilveskoski E, Loimaala A, Mercuri MF, Lehtimaki T, Pasanen M, Nenonen A, et al. Apolipoprotein E polymorphism and carotid artery intima–media thickness in a random sample of middle-aged men. Atherosclerosis 2000;153(1):147–53.
- Schmitz G, Langmann T. Pharmacogenomics of cholesterol-lowering therapy. Vascul Pharmacol 2006;44(2):75-89.
- Utermann G. Apolipoprotein E polymorphism in health and disease. Am Heart J 1987;113:433-40.
- Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622-30.
- Liberopoulos E, Siamopoulos K, Elisaf M. Apolipoprotein E and renal disease. Am J Kidney Dis 2004;43:223-33.
- Nieminen T, Kahonen M, Viiri LE, Gronroos P, Lehtimaki T. Pharmacogenetics of apolipoprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease. Pharmacogenomics 2008;9(10):1475–86.
- Pena R, Lahoz C, Mostaza JM, Jimenez J, Subirats E, Pinto X, et al. Effect of apoE genotype on the hypolipidaemic response to pravastatin in an out patient stetting. J Inter Med 2002;251:518–25.
- Sanllehy C, Casals E, Rodriguez-Villar C, Zambon D, Ojuel J, Ballesta AM, et al. Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. Metabolism 1998;47:560-65.
- Zintzaras E, Kitsios GD, Triposkiadis F, Lau J, Raman G. APOE gene polymorphisms and response to statin therapy. Pharmacogenomics J 2009;9(4):248–57.
- Mangravite LM, Krauss RM. Pharmacogenomics of statin response. Curr Opin Lipidol 2007;18(4):409-14.
References
Kajinami K, Akao H, Polisecki E, Schaefer J. Pharmacogenomics of statin responsiveness. Am J Cardiol 2005;96(9A):65-70.
Peters BJ, Pett H, Klungel OH, Stricker BH, Psaty BM, Glazer NL, et al. Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI. Atherosclerosis 2011;217(2):458-64.
Fiegenbaum M, da Silveira FR, Van der Sand CR, Van der Sand LC, Ferreira ME, Pires RC, et al. Pharmacogenetic study of apolipoprotein E, cholesteryl ester transfer protein and hepatic lipase genes and simvastatin therapy in Brazilian subjects. Clin Chim Acta 2005;362(1-2):182-8.
Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J 2006;6(6):360-74.
Postmus I, Verschuren JJ, de Craen AJ, Slagboom PE, Westendorp RG, Jukema JW, et al. Pharmacogenetics of statins: achievements, whole-genome analyses and future perspectives. Pharmacogenomics 2012;13(7):831-40.
Voora D, Shah SH, Reed CR, Zhai J, Crosslin DR, Messer C, et al. Pharmacogenetic predictors of statin-mediated low-densitylipoprotein cholesterol reduction and dose response. Circ Cardiovasc Genet 2008;1(2):100-6.
Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoproteincholesterol response to simvastatin treatment. Circulation 2008;117(12):1537-44.
Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP Jr, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004;291:2821–27.
Thompson JF, Man M, Johnson KJ, Wood LS, Lira ME, Lloyd DB, et al. An association study of 43 SNPs in 16 candidate genes with atorvastatin response. Pharmacogenomics J 2005;5:352–58.
Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, Cox DR, et al. Comprehensive whole genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circ Cardiovasc Genet 2009;2(2):173-81.
Christidis DS, Liberopoulos EN, Kakafika AI, Miltiadous GA, Cariolou M, Ganotakis ES, et al. The effect of apolipoprotein E polymorphism on the response to lipid-lowering treatment with atorvastatin or fenofibrate. J Cardiovasc Pharmacol Ther 2006;11(3):211-21.
Saidi S, Slamia LB, Ammou SB, Mahjoub T, Almawi WY. Association of apolipoprotein E gene polymorphism with ischemicstroke involving large-vessel disease and its relation to serum lipidlevels. J Stroke Cerebrovasc Dis 2007;16(4):160-6.
Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, et al. Genome-wide association study of genetic determinants of LDL-cresponse to atorvastatin therapy: importance of Lp(a). J Lipid Res 2012;53(5):1000-11.
Yamauchi K, Tozuka M, Nakabayashi T, Sugano M, Hidaka H, Kondo Y, et al. Apolipoprotein E in cerebrospinal fluid: Relation to phenotype and plasma apolipoprotein E concentrations. Clin Chem 1999;45(4):497-504.
Luc G, Bard JM, Arveiler D, Evans A, Cambou JP, Bingham A, et al. Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study. Arterioscl, Thromb Vas 1994;14:1412-19.
Poduri A, Khullar M, Bahl A, Sehrawat BS, Sharma Y, Talwar KK. Common variants of HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy. DNA Cell Biol 2010;29(10):629-37.
Polisecki E, Muallem H, Maeda N, Peter I, Robertson M, McMahon AD, et al. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Investigators. Genetic variation at the LDL receptor and HMG-CoA reductase geneloci, lipid levels, statin response, and cardiovascular diseaseincidence in PROSPER. Atherosclerosis 2008;200(1):109-14.
Kajinami K, Takekoshi N, Brousseau ME, Schaefer EJ. Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. Atherosclerosis 2004;177(2):219-34.
Lehtimaki T, Moilanen T, Nikkari T, Solakivi T, Porkka K, Ehnholm C, et al. Regional differences in apolipoprotein E polymorphism in Finland. Ann Med 1991;23(1), 61–66.
Ilveskoski E, Loimaala A, Mercuri MF, Lehtimaki T, Pasanen M, Nenonen A, et al. Apolipoprotein E polymorphism and carotid artery intima–media thickness in a random sample of middle-aged men. Atherosclerosis 2000;153(1):147–53.
Schmitz G, Langmann T. Pharmacogenomics of cholesterol-lowering therapy. Vascul Pharmacol 2006;44(2):75-89.
Utermann G. Apolipoprotein E polymorphism in health and disease. Am Heart J 1987;113:433-40.
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622-30.
Liberopoulos E, Siamopoulos K, Elisaf M. Apolipoprotein E and renal disease. Am J Kidney Dis 2004;43:223-33.
Nieminen T, Kahonen M, Viiri LE, Gronroos P, Lehtimaki T. Pharmacogenetics of apolipoprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease. Pharmacogenomics 2008;9(10):1475–86.
Pena R, Lahoz C, Mostaza JM, Jimenez J, Subirats E, Pinto X, et al. Effect of apoE genotype on the hypolipidaemic response to pravastatin in an out patient stetting. J Inter Med 2002;251:518–25.
Sanllehy C, Casals E, Rodriguez-Villar C, Zambon D, Ojuel J, Ballesta AM, et al. Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. Metabolism 1998;47:560-65.
Zintzaras E, Kitsios GD, Triposkiadis F, Lau J, Raman G. APOE gene polymorphisms and response to statin therapy. Pharmacogenomics J 2009;9(4):248–57.
Mangravite LM, Krauss RM. Pharmacogenomics of statin response. Curr Opin Lipidol 2007;18(4):409-14.