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Clinical Implication

Clinical implications of pharmacogenomics of statin treatment

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References

  1. Grundy SM, Cleeman JI, Merz CN, Brewer Jr HB, Clark LT, Hunninghake DB et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227–239.

    PubMed  Google Scholar 

  2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–1278.

    CAS  PubMed  Google Scholar 

  3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497.

  4. LaRosa JC . Statins and risk of coronary heart disease. JAMA 2000; 283: 2935–2936.

    CAS  PubMed  Google Scholar 

  5. American Heart Association. Heart Disease and Stroke Statistics-2006 Update. American Heart Association: Dallas, 2006.

  6. Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 2005; 78: 330–341.

    CAS  PubMed  Google Scholar 

  7. Vermes A, Vermes I . Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors. Am J Cardiovasc Drugs 2004; 4: 247–255.

    CAS  PubMed  Google Scholar 

  8. Lennernas H, Fager G . Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet 1997; 32: 403–425.

    CAS  PubMed  Google Scholar 

  9. White CM . A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol 2002; 42: 963–970.

    CAS  PubMed  Google Scholar 

  10. Lennernas H . Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 2003; 42: 1141–1160.

    PubMed  Google Scholar 

  11. Chong PH, Seeger JD, Franklin C . Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med 2001; 111: 390–400.

    CAS  PubMed  Google Scholar 

  12. Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 2002; 30: 505–512.

    CAS  PubMed  Google Scholar 

  13. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton Jr VP, Ridker PM . Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004; 291: 2821–2827.

    CAS  PubMed  Google Scholar 

  14. Fiegenbaum M, da Silveira FR, Van der Sand CR, Van der Sand LC, Ferreira ME, Pires RC et al. The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment. Clin Pharmacol Ther 2005; 78: 551–558.

    CAS  PubMed  Google Scholar 

  15. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol 2004; 93: 104–107.

    CAS  PubMed  Google Scholar 

  16. Kivisto KT, Niemi M, Schaeffeler E, Pitkala K, Tilvis R, Fromm MF et al. Lipid-lowering response to statins is affected by CYP3A5 polymorphism. Pharmacogenetics 2004; 14: 523–525.

    PubMed  Google Scholar 

  17. 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. Pharmacogenom J 2005; 5: 352–358.

    CAS  Google Scholar 

  18. Wang A, Yu BN, Luo CH, Tan ZR, Zhou G, Wang LS et al. Ile118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients. Eur J Clin Pharmacol 2005; 60: 843–848.

    CAS  PubMed  Google Scholar 

  19. Kirchheiner J, Brockmoller J . Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1–16.

    CAS  PubMed  Google Scholar 

  20. Nordin C, Dahl ML, Eriksson M, Sjoberg S . Is the cholesterol-lowering effect of simvastatin influenced by CYP2D6 polymorphism? Lancet 1997; 350: 29–30.

    CAS  PubMed  Google Scholar 

  21. Geisel J, Kivisto KT, Griese EU, Eichelbaum M . The efficacy of simvastatin is not influenced by CYP2D6 polymorphism. Clin Pharmacol Ther 2002; 72: 595–596.

    PubMed  Google Scholar 

  22. Mulder AB, van den Bergh FA, Vermes I . Response to ‘The efficacy of simvastatin is not influenced by CYP2D6 polymorphism’ by Geisel et al. Clin Pharmacol Ther 2003; 73: 475.

    CAS  PubMed  Google Scholar 

  23. Mulder AB, van Lijf HJ, Bon MA, van den Bergh FA, Touw DJ, Neef C et al. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clin Pharmacol Ther 2001; 70: 546–551.

    CAS  PubMed  Google Scholar 

  24. Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ et al. In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 1997; 25: 1191–1199.

    CAS  PubMed  Google Scholar 

  25. Prueksaritanont T, Ma B, Yu N . The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J Clin Pharmacol 2003; 56: 120–124.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Transon C, Leemann T, Dayer P . In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–215.

    CAS  PubMed  Google Scholar 

  27. Ekins S, Johnston JS, Bahadduri P, D'Souza VM, Ray A, Chang C et al. In vitro and pharmacophore-based discovery of novel hPEPT1 inhibitors. Pharm Res 2005; 22: 512–517.

    CAS  PubMed  Google Scholar 

  28. Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I . Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther 2004; 308: 438–445.

    PubMed  Google Scholar 

  29. Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 2004; 14: 429–440.

    CAS  PubMed  Google Scholar 

  30. Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y et al. Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 2002; 302: 804–813.

    CAS  PubMed  Google Scholar 

  31. Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T . Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 2004; 75: 415–421.

    CAS  PubMed  Google Scholar 

  32. Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 2003; 73: 554–565.

    CAS  PubMed  Google Scholar 

  33. Niemi M, Neuvonen PJ, Hofmann U, Backman JT, Schwab M, Lutjohann D et al. Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenet Genom 2005; 15: 303–309.

    CAS  Google Scholar 

  34. Tachibana-Iimori R, Tabara Y, Kusuhara H, Kohara K, Kawamoto R, Nakura J et al. Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab Pharmacokinet 2004; 19: 375–380.

    CAS  PubMed  Google Scholar 

  35. Schachter M . Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 2005; 19: 117–125.

    CAS  PubMed  Google Scholar 

  36. Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ et al. Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 2005; 33: 537–546.

    CAS  PubMed  Google Scholar 

  37. Hirano M, Maeda K, Hayashi H, Kusuhara H, Sugiyama Y . Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther 2005; 314: 876–882.

    CAS  PubMed  Google Scholar 

  38. Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y . Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol 2005; 68: 800–807.

    CAS  PubMed  Google Scholar 

  39. Kivisto KT, Grisk O, Hofmann U, Meissner K, Moritz KU, Ritter C et al. Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats. Drug Metab Dispos 2005; 33: 1593–1596.

    PubMed  Google Scholar 

  40. Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H et al. Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther 2005; 314: 1059–1067.

    CAS  PubMed  Google Scholar 

  41. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender-specific manner. Am J Cardiol 2004; 93: 1046–1050.

    CAS  PubMed  Google Scholar 

  42. Rodrigues AC, Rebecchi IM, Bertolami MC, Faludi AA, Hirata MH, Hirata RD . High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent. Braz J Med Biol Res 2005; 38: 1389–1397.

    CAS  PubMed  Google Scholar 

  43. Garcia PJ . Pleiotropic effects of statins: moving beyond cholesterol control. Curr Atheroscler Rep 2005; 7: 34–39.

    CAS  PubMed  Google Scholar 

  44. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin. Atherosclerosis 2004; 175: 287–293.

    CAS  PubMed  Google Scholar 

  45. Chaves FJ, Real JT, Garcia-Garcia AB, Civera M, Armengod ME, Ascaso JF et al. Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol. J Clin Endocrinol Metab 2001; 86: 4926–4932.

    CAS  PubMed  Google Scholar 

  46. 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: 219–234.

    CAS  PubMed  Google Scholar 

  47. Miltiadous G, Xenophontos S, Bairaktari E, Ganotakis M, Cariolou M, Elisaf M . Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. Pharmacogenet Genom 2005; 15: 219–225.

    CAS  Google Scholar 

  48. Raal FJ, Pappu AS, Illingworth DR, Pilcher GJ, Marais AD, Firth JC et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis 2000; 150: 421–428.

    CAS  PubMed  Google Scholar 

  49. Vuorio AF, Ojala JP, Sarna S, Turtola H, Tikkanen MJ, Kontula K . Heterozygous familial hypercholesterolaemia: the influence of the mutation type of the low-density-lipoprotein receptor gene and PvuII polymorphism of the normal allele on serum lipid levels and response to lovastatin treatment. J Intern Med 1995; 237: 43–48.

    CAS  PubMed  Google Scholar 

  50. Lahoz C, Pena R, Mostaza JM, Laguna F, Garcia-Iglesias MF, Taboada M et al. Baseline levels of low-density lipoprotein cholesterol and lipoprotein (a) and the AvaII polymorphism of the low-density lipoprotein receptor gene influence the response of low-density lipoprotein cholesterol to pravastatin treatment. Metabolism 2005; 54: 741–747.

    CAS  PubMed  Google Scholar 

  51. Salazar LA, Hirata MH, Quintao EC, Hirata RD . Lipid-lowering response of the HMG-CoA reductase inhibitor fluvastatin is influenced by polymorphisms in the low-density lipoprotein receptor gene in Brazilian patients with primary hypercholesterolemia. J Clin Lab Anal 2000; 14: 125–131.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fiegenbaum M, Silveira FR, Van der Sand CR, Van der Sand LC, Ferreira ME, Pires RC et al. Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes. Pharmacogenomics J 2005; 5: 359–364.

    CAS  PubMed  Google Scholar 

  53. Salek L, Lutucuta S, Ballantyne CM, Gotto Jr AM, Marian AJ . Effects of SREBF-1a and SCAP polymorphisms on plasma levels of lipids, severity, progression and regression of coronary atherosclerosis and response to therapy with fluvastatin. J Mol Med 2002; 80: 737–744.

    CAS  PubMed  Google Scholar 

  54. Fan YM, Laaksonen R, Janatuinen T, Vesalainen R, Nuutila P, Knuuti J et al. Effects of pravastatin therapy on serum lipids and coronary reactivity are not associated with SREBP cleavage-activating protein polymorphism in healthy young men. Clin Genet 2001; 60: 319–321.

    CAS  PubMed  Google Scholar 

  55. Chen SN, Ballantyne CM, Gotto Jr AM, Tan Y, Willerson JT, Marian AJ . A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol 2005; 45: 1611–1619.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 2005; 25: 2654–2660.

    CAS  PubMed  Google Scholar 

  57. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA 2005; 102: 5374–5379.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ballantyne CM . Current and future aims of lipid-lowering therapy: changing paradigms and lessons from the Heart Protection Study on standards of efficacy and safety. Am J Cardiol 2003; 92: 3K–9K.

    CAS  PubMed  Google Scholar 

  59. Carmena R, Roederer G, Mailloux H, Lussier-Cacan S, Davignon J . The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism. Metabolism 1993; 42: 895–901.

    CAS  PubMed  Google Scholar 

  60. De Knijff P, Stalenhoef AF, Mol MJ, Gevers Leuven JA, Smit J, Erkelens DW et al. Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia. Atherosclerosis 1990; 83: 89–97.

    CAS  PubMed  Google Scholar 

  61. Garcia-Otin AL, Civeira F, Aristegui R, Diaz C, Recalde D, Sol JM et al. Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment. Eur J Clin Invest 2002; 32: 421–428.

    CAS  PubMed  Google Scholar 

  62. Ojala JP, Helve E, Ehnholm C, Aalto-Setala K, Kontula KK, Tikkanen MJ . Effect of apolipoprotein E polymorphism and XbaI polymorphism of apolipoprotein B on response to lovastatin treatment in familial and non-familial hypercholesterolaemia. J Intern Med 1991; 230: 397–405.

    CAS  PubMed  Google Scholar 

  63. Ordovas JM, Lopez-Miranda J, Perez-Jimenez F, Rodriguez C, Park JS, Cole T et al. Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy. Atherosclerosis 1995; 113: 157–166.

    CAS  PubMed  Google Scholar 

  64. 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 outpatient setting. J Intern Med 2002; 251: 518–525.

    CAS  PubMed  Google Scholar 

  65. 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: 560–565.

    CAS  PubMed  Google Scholar 

  66. Ye P, Shang Y, Ding X . The influence of apolipoprotein B and E gene polymorphisms on the response to simvastatin therapy in patients with hyperlipidemia. Chin Med Sci J 2003; 18: 9–13.

    CAS  PubMed  Google Scholar 

  67. Maitland-van der Zee AH, Stricker BH, Klungel OH, Mantel-Teeuwisse AK, Kastelein JJ, Hofman A et al. Adherence to and dosing of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors in the general population differs according to apolipoprotein E-genotypes. Pharmacogenetics 2003; 13: 219–223.

    CAS  PubMed  Google Scholar 

  68. Nestel P, Simons L, Barter P, Clifton P, Colquhoun D, Hamilton-Craig I et al. A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin. Atherosclerosis 1997; 129: 231–239.

    CAS  PubMed  Google Scholar 

  69. O'Neill FH, Patel DD, Knight BL, Neuwirth CK, Bourbon M, Soutar AK et al. Determinants of variable response to statin treatment in patients with refractory familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2001; 21: 832–837.

    CAS  PubMed  Google Scholar 

  70. Pedro-Botet J, Schaefer EJ, Bakker-Arkema RG, Black DM, Stein EM, Corella D et al. Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner. Atherosclerosis 2001; 158: 183–193.

    CAS  PubMed  Google Scholar 

  71. Guzman EC, Hirata MH, Quintao EC, Hirata RD . Association of the apolipoprotein B gene polymorphisms with cholesterol levels and response to fluvastatin in Brazilian individuals with high risk for coronary heart disease. Clin Chem Lab Med 2000; 38: 731–736.

    CAS  PubMed  Google Scholar 

  72. Kajinami K, Brousseau ME, Lamon-Fava S, Ordovas JM, Schaefer EJ . Gender-specific effects of estrogen receptor alpha gene haplotype on high-density lipoprotein cholesterol response to atorvastatin: interaction with apolipoprotein AI gene polymorphism. Atherosclerosis 2005; 178: 331–338.

    CAS  PubMed  Google Scholar 

  73. Sorkin SC, Forestiero FJ, Hirata MH, Guzman EC, Cavalli SA, Bertolami MC et al. APOA1 polymorphisms are associated with variations in serum triglyceride concentrations in hypercholesterolemic individuals. Clin Chem Lab Med 2005; 43: 1339–1345.

    CAS  PubMed  Google Scholar 

  74. Boekholdt SM, Kuivenhoven JA, Hovingh GK, Jukema JW, Kastelein JJ, van Tol A . CETP gene variation: relation to lipid parameters and cardiovascular risk. Curr Opin Lipidol 2004; 15: 393–398.

    CAS  PubMed  Google Scholar 

  75. Boekholdt SM, Sacks FM, Jukema JW, Shepherd J, Freeman DJ, McMahon AD et al. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13 677 subjects. Circulation 2005; 111: 278–287.

    CAS  PubMed  Google Scholar 

  76. de Grooth GJ, Zerba KE, Huang SP, Tsuchihashi Z, Kirchgessner T, Belder R et al. The cholesteryl ester transfer protein (CETP) TaqIB polymorphism in the cholesterol and recurrent events study: no interaction with the response to pravastatin therapy and no effects on cardiovascular outcome: a prospective analysis of the CETP TaqIB polymorphism on cardiovascular outcome and interaction with cholesterol-lowering therapy. J Am Coll Cardiol 2004; 43: 854–857.

    CAS  PubMed  Google Scholar 

  77. Freeman DJ, Samani NJ, Wilson V, McMahon AD, Braund PS, Cheng S et al. A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study. Eur Heart J 2003; 24: 1833–1842.

    CAS  PubMed  Google Scholar 

  78. Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 1998; 338: 86–93.

    CAS  PubMed  Google Scholar 

  79. Garcia-Garcia AB, Gonzalez C, Real JT, Martin de Llano JJ, Gonzalez-Albert V, Civera M et al. Influence of microsomal triglyceride transfer protein promoter polymorphism -493 GT on fasting plasma triglyceride values and interaction with treatment response to atorvastatin in subjects with heterozygous familial hypercholesterolaemia. Pharmacogenet Genom 2005; 15: 211–218.

    CAS  Google Scholar 

  80. Ledmyr H, McMahon AD, Ehrenborg E, Nielsen LB, Neville M, Lithell H et al. The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease. Circulation 2004; 109: 2279–2284.

    CAS  PubMed  Google Scholar 

  81. Sing K, Ballantyne CM, Ferlic L, Brugada R, Cushman I, Dunn JK et al. Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of coronary atherosclerosis, response to therapy, and future clinical events. Lipoproteins and Coronary Atherosclerosis Study. Atherosclerosis 1999; 144: 435–442.

    CAS  PubMed  Google Scholar 

  82. Berk II P, Hoogerbrugge N, Stolk RP, Bootsma AH, Jansen H . Atorvastatin dose-dependently decreases hepatic lipase activity in type 2 diabetes: effect of sex and the LIPC promoter variant. Diab Care 2003; 26: 427–432.

    Google Scholar 

  83. Cenarro A, Artieda M, Gonzalvo C, Merino-Ibarra E, Aristegui R, Ganan A et al. Genetic variation in the hepatic lipase gene is associated with combined hyperlipidemia, plasma lipid concentrations, and lipid-lowering drug response. Am Heart J 2005; 150: 1154–1162.

    CAS  PubMed  Google Scholar 

  84. Lahoz C, Pena R, Mostaza JM, Laguna F, Garcia-Iglesias MF, Taboada M et al. The -514C/T polymorphism of the hepatic lipase gene significantly modulates the HDL-cholesterol response to statin treatment. Atherosclerosis 2005; 182: 129–134.

    CAS  PubMed  Google Scholar 

  85. Zambon A, Deeb SS, Brown BG, Hokanson JE, Brunzell JD . Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment. Circulation 2001; 103: 792–798.

    CAS  PubMed  Google Scholar 

  86. Lutucuta S, Ballantyne CM, Elghannam H, Gotto Jr AM, Marian AJ . Novel polymorphisms in promoter region of atp binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy. Circ Res 2001; 88: 969–973.

    CAS  PubMed  Google Scholar 

  87. Wilund KR, Yu L, Xu F, Hobbs HH, Cohen JC . High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholesterolemia and atherosclerosis in Ldlr-/- mice. J Lipid Res 2004; 45: 1429–1436.

    CAS  PubMed  Google Scholar 

  88. Yu L, York J, von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH . Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J Biol Chem 2003; 278: 15565–15570.

    CAS  PubMed  Google Scholar 

  89. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290: 1771–1775.

    CAS  PubMed  Google Scholar 

  90. Gylling H . Cholesterol metabolism and its implications for therapeutic interventions in patients with hypercholesterolaemia. Int J Clin Pract 2004; 58: 859–866.

    CAS  PubMed  Google Scholar 

  91. Gylling H, Miettinen TA . Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients. Atherosclerosis 2002; 160: 477–481.

    CAS  PubMed  Google Scholar 

  92. Kajinami K, Brousseau ME, Nartsupha C, Ordovas JM, Schaefer EJ . ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. J Lipid Res 2004; 45: 653–656.

    CAS  PubMed  Google Scholar 

  93. Miettinen TA, Gylling H, Lindbohm N, Miettinen TE, Rajaratnam RA, Relas H . Serum noncholesterol sterols during inhibition of cholesterol synthesis by statins. J Lab Clin Med 2003; 141: 131–137.

    CAS  PubMed  Google Scholar 

  94. Bray PF, Cannon CP, Goldschmidt-Clermont P, Moye LA, Pfeffer MA, Sacks FM et al. The platelet Pl(A2) and angiotensin-converting enzyme (ACE) D allele polymorphisms and the risk of recurrent events after acute myocardial infarction. Am J Cardiol 2001; 88: 347–352.

    CAS  PubMed  Google Scholar 

  95. Maitland-van der Zee AH, Stricker BH, Klungel OH, Kastelein JJ, Hofman A, Witteman JC et al. Effectiveness of HMG-CoA reductase inhibitors is modified by the ACE insertion deletion polymorphism. Atherosclerosis 2004; 175: 377–379.

    CAS  PubMed  Google Scholar 

  96. Marian AJ, Safavi F, Ferlic L, Dunn JK, Gotto AM, Ballantyne CM . Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study. J Am Coll Cardiol 2000; 35: 89–95.

    CAS  PubMed  Google Scholar 

  97. Walter DH, Schachinger V, Elsner M, Mach S, Dimmeler S, Auch-Schwelk W et al. Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the Pl(A2)allele of the platelet glycoprotein IIIa gene. Eur Heart J 2001; 22: 587–595.

    CAS  PubMed  Google Scholar 

  98. Boekholdt SM, Agema WR, Peters RJ, Zwinderman AH, van der Wall EE, Reitsma PH et al. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation 2003; 107: 2416–2421.

    CAS  PubMed  Google Scholar 

  99. Holloway JW, Yang IA, Ye S . Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction. Pharmacogenet Genomics 2005; 15: 15–21.

    CAS  PubMed  Google Scholar 

  100. Meyboom RH, Edwards IR . Rosuvastatin and the statin wars--the way to peace. Lancet 2004; 364: 1997–1999.

    PubMed  Google Scholar 

  101. Owczarek J, Jasinska M, Orszulak-Michalak D . Drug-induced myopathies. An overview of the possible mechanisms. Pharmacol Rep 2005; 57: 23–34.

    CAS  PubMed  Google Scholar 

  102. Maron DJ, Fazio S, Linton MF . Current perspectives on statins. Circulation 2000; 101: 207–213.

    CAS  PubMed  Google Scholar 

  103. Dobkin BH . Underappreciated statin-induced myopathic weakness causes disability. Neurorehabil Neural Repair 2005; 19: 259–263.

    PubMed  PubMed Central  Google Scholar 

  104. Takeda M, Noshiro R, Onozato ML, Tojo A, Hasannejad H, Huang XL et al. Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors. Eur J Pharmacol 2004; 483: 133–138.

    CAS  PubMed  Google Scholar 

  105. Nagasawa K, Nagai K, Ishimoto A, Fujimoto S . Transport mechanism for lovastatin acid in bovine kidney NBL-1 cells: kinetic evidences imply involvement of monocarboxylate transporter 4. Int J Pharm 2003; 262: 63–73.

    CAS  PubMed  Google Scholar 

  106. Sirvent P, Bordenave S, Vermaelen M, Roels B, Vassort G, Mercier J et al. Simvastatin induces impairment in skeletal muscle while heart is protected. Biochem Biophys Res Commun 2005; 338: 1426–1434.

    CAS  PubMed  Google Scholar 

  107. Bonen A . The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. Eur J Appl Physiol 2001; 86: 6–11.

    CAS  PubMed  Google Scholar 

  108. Sirvent P, Mercier J, Vassort G, Lacampagne A . Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle. Biochem Biophys Res Commun 2005; 329: 1067–1075.

    CAS  PubMed  Google Scholar 

  109. Baker SK . Molecular clues into the pathogenesis of statin-mediated muscle toxicity. Muscle Nerve 2005; 31: 572–580.

    CAS  PubMed  Google Scholar 

  110. Turunen M, Olsson J, Dallner G . Metabolism and function of coenzyme Q. Biochim Biophys Acta 2004; 1660: 171–199.

    CAS  PubMed  Google Scholar 

  111. Kagan T, Davis C, Lin L, Zakeri Z . Coenzyme Q10 can in some circumstances block apoptosis, and this effect is mediated through mitochondria. Ann NY Acad Sci 1999; 887: 31–47.

    CAS  PubMed  Google Scholar 

  112. Rundek T, Naini A, Sacco R, Coates K, DiMauro S . Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004; 61: 889–892.

    PubMed  Google Scholar 

  113. Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993; 33: 226–229.

    CAS  PubMed  Google Scholar 

  114. Nawarskas JJ . HMG-CoA reductase inhibitors and coenzyme Q10. Cardiol Rev 2005; 13: 76–79.

    PubMed  Google Scholar 

  115. Gray DF, Bundgaard H, Hansen PS, Buhagiar KA, Mihailidou AS, Jessup W et al. HMG CoA reductase inhibition reduces sarcolemmal Na(+)-K(+) pump density. Cardiovasc Res 2000; 47: 329–335.

    CAS  PubMed  Google Scholar 

  116. Thompson PD, Clarkson P, Karas RH . Statin-associated myopathy. JAMA 2003; 289: 1681–1690.

    CAS  PubMed  Google Scholar 

  117. Ishikawa C, Ozaki H, Nakajima T, Ishii T, Kanai S, Anjo S et al. A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin. J Hum Genet 2004; 49: 582–585.

    PubMed  Google Scholar 

  118. Morimoto K, Oishi T, Ueda S, Ueda M, Hosokawa M, Chiba K . A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab Pharmacokinet 2004; 19: 453–455.

    CAS  PubMed  Google Scholar 

  119. Wilke RA, Moore JH, Burmester JK . Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet Genomics 2005; 15: 415–421.

    CAS  PubMed  Google Scholar 

  120. Ruano G, Thompson PD, Windemuth A, Smith A, Kocherla M, Holford TR et al. Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis. Pharmacogenomics 2005; 6: 865–872.

    CAS  PubMed  Google Scholar 

  121. Kirchheiner J, Kudlicz D, Meisel C, Bauer S, Meineke I, Roots I et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 2003; 74: 186–194.

    CAS  PubMed  Google Scholar 

  122. Bercovich D, Friedlander Y, Korem S, Houminer A, Hoffman A, Kleinberg L et al. The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia. Atherosclerosis 2005; 185 (1): 97–107.

    PubMed  Google Scholar 

  123. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Atherosclerosis 2005; 180: 407–415.

    CAS  PubMed  Google Scholar 

  124. Leitersdorf E, Eisenberg S, Eliav O, Friedlander Y, Berkman N, Dann EJ et al. Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia. Circulation 1993; 87 (4 Suppl): III35–III44.

    CAS  PubMed  Google Scholar 

  125. 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: 1366–1371.

    CAS  PubMed  Google Scholar 

  126. Lahoz C, Pena R, Mostaza JM, Jimenez J, Subirats E, Pinto X et al. Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy. Atherosclerosis 2003; 168: 289–295.

    CAS  PubMed  Google Scholar 

  127. Mohrschladt MF, van der Sman-de Beer F, Hofman MK, van der Krabben M, Westendorp RG, Smelt AH . TaqIB polymorphism in CETP gene: the influence on incidence of cardiovascular disease in statin-treated patients with familial hypercholesterolemia. Eur J Hum Genet 2005; 13: 877–882.

    CAS  PubMed  Google Scholar 

  128. Carlquist JF, Muhlestein JB, Horne BD, Hart NI, Bair TL, Molhuizen HO et al. The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease. Am Heart J 2003; 146: 1007–1014.

    CAS  PubMed  Google Scholar 

  129. van Venrooij FV, Stolk RP, Banga JD, Sijmonsma TP, van Tol A, Erkelens DW et al. Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes. Diabet Care 2003; 26: 1216–1223.

    CAS  Google Scholar 

  130. Klerkx AH, de Grooth GJ, Zwinderman AH, Jukema JW, Kuivenhoven JA, Kastelein JJ . Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur J Clin Invest 2004; 34: 21–28.

    CAS  PubMed  Google Scholar 

  131. Winkelmann BR, Hoffmann MM, Nauck M, Kumar AM, Nandabalan K, Judson RS et al. Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy. Pharmacogenom J 2003; 3: 284–296.

    CAS  Google Scholar 

  132. Jukema JW, van Boven AJ, Groenemeijer B, Zwinderman AH, Reiber JH, Bruschke AV et al. The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis. REGRESS Study Group, Interuniversity Cardiology Institute, Utrecht, The Netherlands. Regression Growth Evaluation Statin Study. Circulation 1996; 94: 1913–1918.

    CAS  PubMed  Google Scholar 

  133. Malin R, Laaksonen R, Knuuti J, Janatuinen T, Vesalainen R, Nuutila P et al. Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol. Pharmacogenetics 2001; 11: 625–633.

    CAS  PubMed  Google Scholar 

  134. Turban S, Fuentes F, Ferlic L, Brugada R, Gotto AM, Ballantyne CM et al. A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin. Atherosclerosis 2001; 154: 633–640.

    CAS  PubMed  Google Scholar 

  135. Chen S, Tsybouleva N, Ballantyne CM, Gotto Jr AM, Marian AJ . Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. Pharmacogenetics 2004; 14: 61–71.

    CAS  PubMed  Google Scholar 

  136. Agema WR, Wouter Jukema J, de Maat MP, Zwinderman AH, Kastelein JJ, Rabelink TJ et al. Pharmacogenetics of the CD14 endotoxin receptor polymorphism and progression of coronary atherosclerosis. Thromb Haemost 2004; 91: 986–990.

    CAS  PubMed  Google Scholar 

  137. Elghannam H, Tavackoli S, Ferlic L, Gotto Jr AM, Ballantyne CM, Marian AJ . A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary atherosclerosis and its response to therapy. J Mol Med 2000; 78: 562–568.

    CAS  PubMed  Google Scholar 

  138. Takahashi-Yasuno A, Masuzaki H, Miyawaki T, Ogawa Y, Matsuoka N, Hayashi T et al. Leptin receptor polymorphism is associated with serum lipid levels and impairment of cholesterol lowering effect by simvastatin in Japanese men. Diab Res Clin Pract 2003; 62: 169–175.

    CAS  Google Scholar 

  139. Lehtimaki T, Laaksonen R, Janatuinen T, Vesalainen R, Nuutila P, Mattila K et al. Interleukin-1B genotype modulates the improvement of coronary artery reactivity by lipid-lowering therapy with pravastatin: a placebo-controlled positron emission tomography study in young healthy men. Pharmacogenetics 2003; 13: 633–639.

    PubMed  Google Scholar 

  140. de Maat MP, Jukema JW, Ye S, Zwinderman AH, Moghaddam PH, Beekman M et al. Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis. Am J Cardiol 1999; 83: 852–856.

    CAS  PubMed  Google Scholar 

  141. de Maat MP, Kastelein JJ, Jukema JW, Zwinderman AH, Jansen H, Groenemeier B et al. 455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb Vasc Biol 1998; 18: 265–271.

    CAS  PubMed  Google Scholar 

  142. Basso F, Lowe GD, Rumley A, McMahon AD, Humphries SE . Interleukin-6 -174G>C polymorphism and risk of coronary heart disease in West of Scotland coronary prevention study (WOSCOPS). Arterioscler Thromb Vasc Biol 2002; 22: 599–604.

    CAS  PubMed  Google Scholar 

  143. Kunnas TA, Lehtimaki T, Laaksonen R, Ilveskoski E, Janatuinen T, Vesalainen R et al. Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study. J Mol Med 2002; 80: 802–807.

    CAS  PubMed  Google Scholar 

  144. Zito F, Lowe GD, Rumley A, McMahon AD, Humphries SE . Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study. Atherosclerosis 2002; 165: 153–158.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Pharmacogenetics Research Network Grants U-01 HL-69757, funded by the National Heart Lung and Blood Institute, and U-01 GM-61374, funded by the National Institute of General Medicine Sciences.

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Correspondence to R M Krauss.

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Mangravite, L., Thorn, C. & Krauss, R. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J 6, 360–374 (2006). https://doi.org/10.1038/sj.tpj.6500384

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