American Journal of Cardiovascular Drugs

, Volume 13, Issue 3, pp 151–162 | Cite as

Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders

Current Opinion


Cardiovascular disease is a leading cause of death worldwide. Many pharmacologic therapies are available that aim to reduce the risk of cardiovascular disease but there is significant inter-individual variation in drug response, including both efficacy and toxicity. Pharmacogenetics aims to personalize medication choice and dosage to ensure that maximum clinical benefit is achieved whilst side effects are minimized. Over the past decade, our knowledge of pharmacogenetics in cardiovascular therapies has increased significantly. The anticoagulant warfarin represents the most advanced application of pharmacogenetics in cardiovascular medicine. Prospective randomized clinical trials are currently underway utilizing dosing algorithms that incorporate genetic polymorphisms in cytochrome P450 (CYP)2C9 and vitamin k epoxide reductase (VKORC1) to determine warfarin dosages. Polymorphisms in CYP2C9 and VKORC1 account for approximately 40 % of the variance in warfarin dose. There is currently significant controversy with regards to pharmacogenetic testing in anti-platelet therapy. Inhibition of platelet aggregation by aspirin in vitro has been associated with polymorphisms in the cyclo-oxygenase (COX)-1 gene. However, COX-1 polymorphisms did not affect clinical outcomes in patients prescribed aspirin therapy. Similarly, CYP2C19 polymorphisms have been associated with clopidogrel resistance in vitro, and have shown an association with stent thrombosis, but not with other cardiovascular outcomes in a consistent manner. Response to statins has been associated with polymorphisms in the cholesterol ester transfer protein (CETP), apolipoprotein E (APOE), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, calmin (CLMN) and apolipoprotein-CI (APOC1) genes. Although these genes contribute to the variation in lipid levels during statin therapy, their effects on cardiovascular outcomes requires further investigation. Polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene is associated with increased statin exposure and simvastatin-induced myopathy. Angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists (β-blockers) are medications that are important in the management of hypertension and heart failure. Insertion and deletion polymorphisms in the ACE gene are associated with elevated and reduced serum levels of ACE, respectively. No significant association was reported between the polymorphism and blood pressure reduction in patients treated with perindopril. However, a pharmacogenetic score incorporating single nucleotide polymorphisms (SNPs) in the bradykinin type 1 receptor gene and angiotensin-II type I receptor gene predicted those most likely to benefit and suffer harm from perindopril therapy. Pharmacogenetic studies into β-blocker therapy have focused on variations in the β1-adrenoceptor gene and CYP2D6, but results have been inconsistent. Pharmacogenetic testing for ACE inhibitor and β-blocker therapy is not currently used in clinical practice. Despite extensive research, no pharmacogenetic tests are currently in clinical practice for cardiovascular medicines. Much of the research remains in the discovery phase, with researchers struggling to demonstrate clinical utility and validity. This is a problem seen in many areas of therapeutics and is because of many factors, including poor study design, inadequate sample sizes, lack of replication, and heterogeneity amongst patient populations and phenotypes. In order to progress pharmacogenetics in cardiovascular therapies, researchers need to utilize next-generation sequencing technologies, develop clear phenotype definitions and engage in multi-center collaborations, not only to obtain larger sample sizes but to replicate associations and confirm results across different ethnic groups.


Warfarin Percutaneous Coronary Intervention Clopidogrel Statin Therapy Dabigatran 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Vincent Yip is an MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca, and the Medical Evaluation Unit.

Conflicts of interest

The authors have no conflict of interest relevant to the content of this article.


  1. 1.
    Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics—2011 update. Circulation. 2011;123(4):e18–209.PubMedCrossRefGoogle Scholar
  2. 2.
    Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol. 2003;41(9):1633–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Kaminsky LS, Zhang Z-Y. Human P450 metabolism of warfarin. Pharmacol Therap. 1997;73(1):67–74.CrossRefGoogle Scholar
  4. 4.
    Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol. 1992;5(1):54–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys. 1996;333(2):447–58.PubMedCrossRefGoogle Scholar
  6. 6.
    Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics. 1994;4(1):39–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Garcia-Martin E, Martinez C, Ladero JM, Agundez JAG. Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. Mol Diagn Ther. 2006;10(1):29–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2009;65(4):365–75.PubMedCrossRefGoogle Scholar
  9. 9.
    Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K, Kurabayashi M, et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Therap. 2006;80(2):169–78.CrossRefGoogle Scholar
  10. 10.
    Momary KM, Shapiro NL, Viana MAG, Nutescu EA, Helgason CM, Cavallari LH. Factors influencing warfarin dose requirements in African-Americans. Pharmacogenomics. 2007;8(11):1535–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Li T, Chang C-y, Jin D-y, Lin P-j, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427(6974):541–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Peiz H-j, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427(6974):537–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 Haplotypes on Transcriptional Regulation and Warfarin Dose. N Engl J Med. 2005;352(22):2285–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee M-TM, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood. 2010;115(18):3827–34.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement: a systematic review and meta analysis. Thromb Res. 2010;125(4):e159–66.PubMedCrossRefGoogle Scholar
  16. 16.
    Cooper GM, Johnson JA, Langaee TY, Feng H, Stanaway IB, Schwarz UI, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood. 2008;112(4):1022–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 2009;5(3):1–9.CrossRefGoogle Scholar
  18. 18.
    Cha P-C, Mushiroda T, Takahashi A, Kubo M, Minami S, Kamatani N, et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet. 2010;19(23):4735–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Liang R, Wang C, Zhao H, Huang J, Hu D, Sun Y. Influence of CYP4F2 genotype on warfarin dose requirement: a systematic review and meta-analysis. Thromb Res. 2012;130(1):38–44.PubMedCrossRefGoogle Scholar
  20. 20.
    The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360(8):753–64.CrossRefGoogle Scholar
  21. 21.
    Michaud V, Vanier MC, Brouillette D, Roy D, Verret L, Noel N, et al. Combination of phenotype assessments and CYP2C9-VKORC1 polymorphisms in the determination of warfarin dose requirements in heavily medicated patients. Clin Pharmacol Therap. 2008;83(5):740–8.CrossRefGoogle Scholar
  22. 22.
    Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJR, Bumpstead S, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2009;113(4):784–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116(22):2563–70.PubMedCrossRefGoogle Scholar
  24. 24.
    Huang SW, Chen HS, Wang XQ, Huang L, Xu DL, Hu XJ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics. 2009;19(3):226–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Beasley BN, Unger EF, Temple R. Anticoagulant options: why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med. 2011;364(19):1788–90.PubMedCrossRefGoogle Scholar
  26. 26.
    European Medicines Agency. Pradaxa product information 2012 (online). http://wwwemaeuropaeu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059pdf. Accessed 27 Nov 2012.
  27. 27.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.PubMedCrossRefGoogle Scholar
  29. 29.
    Radecki RP. Dabigatran: uncharted waters and potential harms. Ann Int Med. 2012;157(1):66–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Freeman JV, Zhu RP, Owens DK, Garber AM, Hutton DW, Go AS, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Int Med. 2011;154(1):1–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation. 2011;123(22):2562–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Sorensen SV, Kansal AR, Connolly S, Peng SY, Linnehan J, Bradley-Kennedy C, et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective. Thromb Haemost. 2011;105(5):908–19.PubMedCrossRefGoogle Scholar
  33. 33.
    Kamel H, Johnston SC, Easton JD, Kim AS. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack. Stroke. 2012;43(3):881–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Adcock AK, Lee-Iannotti JK, Aguilar MI, Hoffman-Snyder CR, Wingerchuk DM, Wellik KE, et al. Is dabigatran cost effective compared with warfarin for stroke prevention in atrial fibrillation? A critically appraised topic. Neurologist. 2012;18(2):102–7.PubMedCrossRefGoogle Scholar
  35. 35.
    You JHS, Tsui KKN, Wong RSM, Gergory C. Cost-effectiveness of dabigatran versus genotype-guided management of warfarin therapy for stroke prevention in patients with atrial fibrillation. PLoS ONE. 2012;7(6):1–9.Google Scholar
  36. 36.
    Pink J, Lane S, Pirmohamed M, Hughes DA. Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses. BMJ. 2011;31(343):d6333.CrossRefGoogle Scholar
  37. 37.
    Kansal AR, Sorensen SV, Gani R, Robinson P, Pan F, Plumb JM, et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation. Heart. 2012;98(7):573–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Langkilde LK, Bergholdt Asmussen M, Overgaard M. Cost-effectiveness of dabigatran etexilate for stroke prevention in non-valvular atrial fibrillation: applying RE-LY to clinical practice in Denmark. J Med Econ. 2012;15(4):695–703.PubMedCrossRefGoogle Scholar
  39. 39.
    González-Juanatey JR, Álvarez-Sabin J, Lobos JM, et al. Cost-effectiveness of dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain (in Spanish). Rev Esp Cardiol (Engl Ed). 2012;65(10):901–10.CrossRefGoogle Scholar
  40. 40.
    Lee S, Anglade MW, Pham D, Pisacane R, Kluger J, Coleman CI. Cost-effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol. 2012;110(6):845–51.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee S, Anglade MW, Meng J, Hagstrom K, Kluger J, Coleman CI. Cost-effectiveness of apixaban compared with aspirin for stroke prevention in atrial fibrillation among patients unsuitable for warfarin. Circ Cardiovasc Qual Outcomes. 2012;5(4):472–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357(24):2482–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109(25):3171–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J. 2007;28(14):1702–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci. 1975;72(8):3073–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Therap. 2003;73(1):122–30.CrossRefGoogle Scholar
  47. 47.
    Lepäntalo A, Mikkelsson J, Reséndiz JC, Viiri L, Backman JT, Kankuri E, et al. Polymorphisms of COX-I and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost. 2006;95(2):253–9.PubMedGoogle Scholar
  48. 48.
    Clappers N, Van Oijen MGH, Sundaresan S, Brouwer MA, Te Morsche RHM, Keuper W, et al. The C50T polymorphism of the cyclooxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl salicylic acid. Thromb Haemost. 2008;100(1):70–5.PubMedGoogle Scholar
  49. 49.
    Calvete JJ. Clues for understanding the structure and function of a prototypic human integrin: the platelet glycoprotein IIb/IIIa complex. Thromb Haemost. 1994;72(1):1–15.PubMedGoogle Scholar
  50. 50.
    Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive systematic review. Br J Clin Pharmacol. 2008;66(2):222–32.PubMedCrossRefGoogle Scholar
  51. 51.
    Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol. 2010;50(2):126–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Snoep JD, Hovens MMC, Eikenboom JCJ, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J. 2007;154(2):221–31.PubMedCrossRefGoogle Scholar
  53. 53.
    Hulot J-S, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Simon T, Verstuyft C, Mary-krause M, Quteineh L, Drouet E, Méneveau N, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363–75.PubMedCrossRefGoogle Scholar
  55. 55.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354–62.PubMedCrossRefGoogle Scholar
  56. 56.
    Tiroch KA, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schömig A, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J. 2010;160(3):506–12.PubMedCrossRefGoogle Scholar
  57. 57.
    Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376(9749):1320–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849–58.PubMedCrossRefGoogle Scholar
  59. 59.
    Verschuren JJW, Boden H, Wessels JAM, van der Hoeven BL, Trompet S, Heijmans BT, et al. Value of platelet pharmacogenetics in common clinical practice of patients with ST-segment elevation myocardial infarction. Int J Cardiol (Epub 2012 Aug 29).Google Scholar
  60. 60.
    US FDA. Plavix (clopidogrel): reduced effectiveness in patients who are poor metabolizers of the drug. 2010 Mar 12 (online). Accessed 20 Jun 2012.
  61. 61.
    Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “Boxed Warning”. A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2010;56(4):321–41.PubMedCrossRefGoogle Scholar
  62. 62.
    Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;306(24):2704–14.PubMedCrossRefGoogle Scholar
  63. 63.
    Mega JL, Simon T, Collet J-P, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821–30.PubMedCrossRefGoogle Scholar
  64. 64.
    Gladding P, White H, Voss J, Ormiston J, Stewart J, Ruygrok P, et al. Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study. JACC Cardiovasc Interv. 2009;2(11):1095–101.PubMedCrossRefGoogle Scholar
  65. 65.
    Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. 2012;379(9827):1705–11.PubMedCrossRefGoogle Scholar
  66. 66.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel. Circulation. 2009;119(19):2553–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Fuster V, Sweeny JM. Clopidogrel and the reduced-function cyp2c19 genetic variant: a limited piece of the overall therapeutic puzzle. JAMA. 2010;304(16):1839–40.PubMedCrossRefGoogle Scholar
  68. 68.
    Baigent C, Keech A, Kearney PM, Blackwell L, 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(9493):1267–78.PubMedCrossRefGoogle Scholar
  69. 69.
    Thompson GR, O’Neill F, Seed M. Why some patients respond poorly to statins and how this might be remedied. Eur Heart J. 2002;23(3):200–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8 Suppl 1):S52–60.CrossRefGoogle Scholar
  71. 71.
    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. Circulation. 2005;111(3):278–87.PubMedCrossRefGoogle Scholar
  72. 72.
    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(2):86–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Regieli JJ, Jukema JW, Grobbee DE, Kastelein JJP, Kuivenhoven JA, Zwinderman AH, et al. CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. Eur Heart J. 2008;29(22):2792–9.PubMedCrossRefGoogle Scholar
  74. 74.
    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.PubMedCrossRefGoogle Scholar
  75. 75.
    Nieminen T, Kähönen M, Viiri LE, Grönroos P, Lehtimäki T. Pharmacogenetics of apolipoprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease. Pharmacogenomics. 2008;9(10):1475–86.PubMedCrossRefGoogle Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    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.PubMedCrossRefGoogle Scholar
  78. 78.
    Di Chasman PD, Subrahmanyan L, Cook NR, Stanton VP Jr, Ridker P. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004;291(23):2821–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Donnelly LA, Doney ASF, Dannfald J, Whitley AL, Lang CC, Morris AD, et al. A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study. Pharmacogenet Genomics. 2008;18(12):1021–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Barber MJ, Mangravite LM, Hyde CL, Chasman DI, Smith JD, McCarty CA, et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS ONE. 2010;5(3):1–10.CrossRefGoogle Scholar
  81. 81.
    Ishisaki Z, Takaishi M, Furuta I, Huh N-h. Calmin, a protein with calponin homology and transmembrane domains expressed in maturing spermatogenic cells. Genomics. 2001;74(2):172–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Takaishi M, Ishisaki Z, Yoshida T, Takata Y, Huh N-h. Expression of calmin, a novel developmentally regulated brain protein with calponin-homology domains. Mol Brain Res. 2003;112(1–2):146–52.PubMedCrossRefGoogle Scholar
  83. 83.
    Conde-Knape K, Bensadoun A, Sobel JH, Cohn JS, Shachter NS. Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase. J Lipid Res. 2002;43(12):2136–45.PubMedCrossRefGoogle Scholar
  84. 84.
    Jong MC, Gijbels MJ, Dahlmans VE, Gorp PJ, Koopman SJ, Ponec M, et al. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1. J Clin Invest. 1998;101(1):145–52.PubMedCrossRefGoogle Scholar
  85. 85.
    König J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol. 2000;278(1):G156–64.PubMedGoogle Scholar
  86. 86.
    Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82(6):726–33.PubMedCrossRefGoogle Scholar
  87. 87.
    Ho R, Choi L, Lee W, Mayo G, Schwarz U, Tirona R, et al. Effect of drug transporter genotypes on pravastatin disposition in European- and African–American participants. Pharmacogenet Genomics. 2007;17(8):647–56.Google Scholar
  88. 88.
    Pasanen M, Neuvonen M, Neuvonen P, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16(12):873–9.PubMedCrossRefGoogle Scholar
  89. 89.
    The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789–99.CrossRefGoogle Scholar
  90. 90.
    Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54(17):1609–16.PubMedCrossRefGoogle Scholar
  91. 91.
    Niemi M. Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Therap. 2010;87(1):130–3.CrossRefGoogle Scholar
  92. 92.
    National Institute for Health and Clinical Excellence. CG127: hypertension – clinical management of primary hypertension in adults. 2011 (online). Accessed 27 Nov 2012.
  93. 93.
    Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Harrap SB, Tzourio C, Cambien F, Poirier O, Raoux S, Chalmers J, et al. The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. Hypertension. 2003;42(3):297–303.PubMedCrossRefGoogle Scholar
  95. 95.
    Bis JC, Smith NL, Psaty BM, Heckbert SR, Edwards KL, Lemaitre RN, et al. Angiotensinogen Met235Thr polymorphism, angiotensin-converting enzyme inhibitor therapy, and the risk of nonfatal stroke or myocardial infarction in hypertensive patients. Am J Hypertens. 2003;16(12):1011–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Schelleman H, Klungel OH, Witteman JC, Breteler MM, Yazdanpanah M, Danser AH, et al. Angiotensinogen M235T polymorphism and the risk of myocardial infarction and stroke among hypertensive patients on ACE-inhibitors or β-blockers. Eur J Human Genet. 2007;15(4):478–84.CrossRefGoogle Scholar
  97. 97.
    Brugts JJ, Isaacs A, Boersma E, van Duijn CM, Uitterlinden AG, Remme W, et al. Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease. Eur Heart J. 2010;31(15):1854–64.PubMedCrossRefGoogle Scholar
  98. 98.
    Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascular protection using beta-blockers: a critical review of the evidence. J Am Coll Cardiol. 2007;50(7):563–72.PubMedCrossRefGoogle Scholar
  99. 99.
    Johnson JA, Liggett SB. Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin Pharmacol Ther. 2011;89(3):366–78.PubMedCrossRefGoogle Scholar
  100. 100.
    Chen L, Meyers D, Javorsky G, Bursto D, Lolekha P, Lucas M, et al. Arg389Gly-beta(1)-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol. Pharmacogenet Genomics. 2007;17:941–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Muthumala A, Drenos F, Elliott PM, Humphries SE. Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis. Eur J Heart Fail. 2008;10(1):3–13.PubMedCrossRefGoogle Scholar
  102. 102.
    Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, et al. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci USA. 2006;103(30):11288–93.PubMedCrossRefGoogle Scholar
  103. 103.
    MERIT-HF Study Group. An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail. 2003;5(4):463.CrossRefGoogle Scholar
  104. 104.
    Liu J, Liu Z-Q, Yu B-N, Xu F-H, Mo W, Zhou G, et al. Beta1-adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin Pharmacol Therap. 2006;80(1):23–32.CrossRefGoogle Scholar
  105. 105.
    Johnson JA, Zineh I, Puckett BJ, McGorray SP, Yarandi HN, Pauly DF. beta]1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol[ast. Clin Pharmacol Ther. 2003;74(1):44–52.PubMedCrossRefGoogle Scholar
  106. 106.
    Sofowora GG, Dishy V, Muszkat M, Xie HG, Kim RB, Harris PA, et al. A common [beta]1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to [beta]-blockade[ast]. Clin Pharmacol Ther. 2003;73(4):366–71.PubMedCrossRefGoogle Scholar
  107. 107.
    Karlsson J, Lind L, Hallberg P, Michaëlsson K, Kurland L, Kahan T, et al. Beta1-adrenergic receptor gene polymorphisms and response to Beta1-adrenergic receptor blockade in patients with essential hypertension. Clin Cardiol. 2004;27(6):347–50.PubMedCrossRefGoogle Scholar
  108. 108.
    Filigheddu F, Argiolas G, Degortes S, Zaninello R, Frau F, Pitzoi S, et al. Haplotypes of the adrenergic system predict the blood pressure response to β-blockers in women with essential hypertension. Pharmacogenomics. 2010;11(3):319–25.PubMedCrossRefGoogle Scholar
  109. 109.
    Pacanowski MA, Gong Y, Cooper-DeHoff RM, Schork NJ, Shriver MD, Langaee TY, et al. [beta]-adrenergic receptor gene polymorphisms and [beta]-blocker treatment outcomes in hypertension. Clin Pharmacol Ther. 2008;84(6):715–21.PubMedCrossRefGoogle Scholar
  110. 110.
    Magnusson Y, Levin MC, Eggertsen R, Nystrom E, Mobini R, Schaufelberger M, et al. Ser49Gly of [beta]1-adrenergic receptor is associated with effective [beta]-blocker dose in dilated cardiomyopathy[ast]. Clin Pharmacol Ther. 2005;78(3):221–31.PubMedCrossRefGoogle Scholar
  111. 111.
    de Groote P, Helbecque N, Lamblin N, Hermant X, Mc Fadden E, Foucher-Hossein C, et al. Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenet Genomics. 2005;15:137–42.PubMedCrossRefGoogle Scholar
  112. 112.
    Rau T, Wuttke H, Michels LM, Werner U, Bergmann K, Kreft M, et al. Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study. Clin Pharmacol Ther. 2008;85(3):269–72.PubMedCrossRefGoogle Scholar
  113. 113.
    Johnsson G, Regàrdh C. Clinical pharmacokinetics of beta-adrenoreceptor blocking drugs. Clin Pharmacokinet. 1976;1(4):233–63.PubMedCrossRefGoogle Scholar
  114. 114.
    Goryachkina K, Burbello A, Boldueva S, Babak S, Bergman U, Bertilsson L. CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction. Eur J Clin Pharmacol. 2008;64(12):1163–73.PubMedCrossRefGoogle Scholar
  115. 115.
    Pirmohamed M. Acceptance of biomarker-based tests for application in clinical practice: criteria and obstacles. Clin Pharmacol Therap. 2010;88(6):862–6.CrossRefGoogle Scholar
  116. 116.
    Verschuren JJW, Trompet S, Wessels JAM, Guchelaar H-J, de Maat MPM, Simoons ML, et al. A systematic review on pharmacogenetics in cardiovascular disease: is it ready for clinical application? Eur Heart J. 2012;33(2):165–75.PubMedCrossRefGoogle Scholar
  117. 117.
    Johnson JA, Lima JJ. Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges. Pharmacogenetics. 2003;13(9):525–34.PubMedCrossRefGoogle Scholar
  118. 118.
    Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther. 2008;84(3):362–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of Molecular and Clinical PharmacologyUniversity of LiverpoolLiverpoolUK
  2. 2.The Wolfson Centre for Personalised Medicine, Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK

Personalised recommendations