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Pharmacogenomics and Cardiovascular Disease

  • Peter WeekeEmail author
  • Dan M. Roden
Cardiovascular Genomics (C O'Donnell, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cardiovascular Genomics

Abstract

Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established critical pathways and specific loci modulating therapeutic responses to commonly used drugs such as clopidogrel, warfarin, and statins. In addition, genomic approaches have defined mechanisms and genetic variants underlying important toxicities with these and other drugs. These findings have not only resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described to date might be deployed in clinical decision making.

Keywords

Pharmacogenomics Polymorphism Genetics Clopidogrel Warfarin Statin Beta-blocker, Anti-arrhythmic agents Cardiovascular disease Drug responsiveness Toxicity 

Clinical Trial Acronyms

BEST

Beta-Blocker Evaluation of Survival Trial Among Patients on Bucindolol

PERGENE

Perindopril Genetic Association Study

PROGRESS

Perindopril Protection Against Recurrent Stroke Study

Notes

Acknowledgment

Peter Weeke is funded by an unrestrictive grant from the Tryg Foundation (J.nr. 7343–09, TrygFonden, Denmark). Supported in part by U19 HL065962. Dan M. Roden has received grant support from NIH.

Compliance with Ethics Guidelines

Conflict of Interest

Peter Weeke declares that he has no conflict of interest.

Dan M. Roden has received the following patents/royalties: U.S. Letters Patents No. 6456542, issued October 1, 2002 for ‘Method of Screening for Susceptibility to Drug-Induced Cardiac Arrhythmia.’

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Hulot JS, Bura A, Villard E, 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
  4. 4.
    Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5(12):2429–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Harmsze A, van Werkum JW, Bouman HJ, et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics. 2010;20(1):18–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849–57.PubMedCrossRefGoogle Scholar
  8. 8.
    Simon T, Bhatt DL, Bergougnan L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther. 2011;90(2):287–95.PubMedCrossRefGoogle Scholar
  9. 9.
    •• Scott SA, Sangkuhl K, Gardner EE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328–32. Guidelines incorporating genetic variation in CYP2C19 on clopidogrel directed therapy.PubMedCrossRefGoogle Scholar
  10. 10.
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354–62.PubMedCrossRefGoogle Scholar
  11. 11.
    Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373(9660):309–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010;56(2):134–43.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Mega JL, Simon T, Collet JP, 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. Carriers of the CYP2C19*2 risk allele who received clopidogrel post-PCI had a significantly increased risk of a major cardiovascular event, most notably stent thrombosis.PubMedCrossRefGoogle Scholar
  14. 14.
    • Delaney JT, Ramirez AH, Bowton E, et al. Predicting clopidogrel response using DNA samples linked to an electronic health record. Clin Pharmacol Ther. 2012;91(2):257–63. Confirmed findings on clopidogrel resistance in ABCB1 and CYP2C19 using a real-world population identified from electronic health records coupled with genetic information. No evidence of clopidogrel resistance was found for PON1.PubMedCrossRefGoogle Scholar
  15. 15.
    Wallentin L, James S, Storey RF, 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
  16. 16.
    Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010;363(18):1704–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Ellis KJ, Stouffer GA, McLeod HL, Lee CR. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. Pharmacogenomics. 2009;10(11):1799–817.PubMedCrossRefGoogle Scholar
  18. 18.
    Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121(4):512–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Taubert D, von Beckerath N, Grimberg G, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006;80(5):486–501.PubMedCrossRefGoogle Scholar
  20. 20.
    Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363–75.PubMedCrossRefGoogle Scholar
  21. 21.
    •• Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376(9749):1312–9. ABCB1 associated with adverse cardiovascular events independent of genetic variation in CYP2C19 among clopidogrel treated ACS patients.PubMedCrossRefGoogle Scholar
  22. 22.
    Tiroch KA, Sibbing D, Koch W, 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
  23. 23.
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119(19):2553–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Rudez G, Bouman HJ, van Werkum JW, et al. Common variation in the platelet receptor P2RY12 gene is associated with residual on-clopidogrel platelet reactivity in patients undergoing elective percutaneous coronary interventions. Circ Cardiovasc Genet. 2009;2(5):515–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011;17(1):110–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Sibbing D, Koch W, Massberg S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J. 2011;32(13):1605–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Holmes Jr DR, 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. Circulation. 2010;122(5):537–57.PubMedCrossRefGoogle Scholar
  28. 28.
    • Pulley JM, Denny JC, Peterson JF, et al. Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin Pharmacol Ther. 2012;92(1):87–95. Description of the Vanderbilt PREDICT project aimed at implementing and evaluating strategies for personalized medicine.PubMedCrossRefGoogle Scholar
  29. 29.
    Rost S, Fregin A, Ivaskevicius V, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427(6974):537–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Schalekamp T, de Boer A. Pharmacogenetics of oral anticoagulant therapy. Curr Pharm Des. 2010;16(2):187–203.PubMedCrossRefGoogle Scholar
  31. 31.
    Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287(13):1690–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352(22):2285–93.PubMedCrossRefGoogle Scholar
  33. 33.
    Shehab N, Sperling LS, Kegler SR, Budnitz DS. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010;170(21):1926–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics. 2002;12(3):251–63.PubMedCrossRefGoogle Scholar
  35. 35.
    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
  36. 36.
    Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet. 2007;121(1):23–34.PubMedCrossRefGoogle Scholar
  37. 37.
    Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353(9154):717–9.PubMedCrossRefGoogle Scholar
  38. 38.
    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
  39. 39.
    Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA, Sadee W. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood. 2008;112(4):1013–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Scott SA, Edelmann L, Kornreich R, Desnick RJ. Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations. Am J Hum Genet. 2008;82(2):495–500.PubMedCrossRefGoogle Scholar
  41. 41.
    McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol. 2009;75(6):1337–46.PubMedCrossRefGoogle Scholar
  42. 42.
    Kringen MK, Haug KB, Grimholt RM, et al. Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. J Biomed Biotechnol. 2011;2011:739751.PubMedCrossRefGoogle Scholar
  43. 43.
    Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84(3):326–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2009;113(4):784–92.PubMedCrossRefGoogle Scholar
  45. 45.
    •• Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90(4):625–9. Guidelines incorporating genetic variation in CYP2C9 and VKORC1 in warfarin directed therapy.PubMedCrossRefGoogle Scholar
  46. 46.
    Warfarin label information [Updated January 22, 2010].Google Scholar
  47. 47.
    van Schie RM, Wadelius MI, Kamali F, et al. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics. 2009;10(10):1687–95.PubMedCrossRefGoogle Scholar
  48. 48.
    • French B, Joo J, Geller NL, et al. Statistical design of personalized medicine interventions: the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Trials. 2010;11:108. Study utilizing genetic information in each individual to guide warfarin therapy. Google Scholar
  49. 49.
    Simon JA, Lin F, Hulley SB, et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol. 2006;97(6):843–50.PubMedCrossRefGoogle Scholar
  50. 50.
    Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J. 2006;6(6):360–74.PubMedCrossRefGoogle Scholar
  51. 51.
    Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton Jr VP, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004;291(23):2821–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Krauss RM, Mangravite LM, Smith JD, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation. 2008;117(12):1537–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Medina MW, Gao F, Ruan W, Rotter JI, Krauss RM. Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin. Circulation. 2008;118(4):355–62.PubMedCrossRefGoogle Scholar
  54. 54.
    Thompson JF, Hyde CL, Wood LS, 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
  55. 55.
    Utermann G. Apolipoprotein E polymorphism in health and disease. Am Heart J. 1987;113(2 Pt 2):433–40.PubMedCrossRefGoogle Scholar
  56. 56.
    Voora D, Shah SH, Reed CR, et al. Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response. Circ Cardiovasc Genet. 2008;1(2):100–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Zintzaras E, Kitsios GD, Triposkiadis F, Lau J, Raman G. APOE gene polymorphisms and response to statin therapy. Pharm J. 2009;9(4):248–57.Google Scholar
  58. 58.
    Iakoubova OA, Robertson M, Tong CH, et al. KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study. Eur J Cardiovasc Prev Rehabil. 2010;17(4):455–61.PubMedCrossRefGoogle Scholar
  59. 59.
    Iakoubova OA, Sabatine MS, Rowland CM, et al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2008;51(4):449–55.PubMedCrossRefGoogle Scholar
  60. 60.
    Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll Cardiol. 2008;51(4):435–43.PubMedCrossRefGoogle Scholar
  61. 61.
    Assimes TL, Holm H, Kathiresan S, et al. Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case–control studies. J Am Coll Cardiol. 2010;56(19):1552–63.PubMedCrossRefGoogle Scholar
  62. 62.
    Ridker PM, MacFadyen JG, Glynn RJ, Chasman DI. Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of rosuvastatin in primary prevention. Circ Cardiovasc Genet. 2011;4(3):312–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Mega JL, Morrow DA, Brown A, Cannon CP, Sabatine MS. Identification of genetic variants associated with response to statin therapy. Arterioscler Thromb Vasc Biol. 2009;29(9):1310–5.PubMedCrossRefGoogle Scholar
  64. 64.
    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(8):1046–50.PubMedCrossRefGoogle Scholar
  65. 65.
    Kondo C, Suzuki H, Itoda M, et al. Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res. 2004;21(10):1895–903.PubMedCrossRefGoogle Scholar
  66. 66.
    Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C–60C.PubMedCrossRefGoogle Scholar
  67. 67.
    Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001;276(38):35669–75.PubMedCrossRefGoogle Scholar
  68. 68.
    Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16(12):873–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008;359(8):789–99.PubMedCrossRefGoogle Scholar
  70. 70.
    Voora D, Shah SH, Spasojevic I, 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
  71. 71.
    Wilke RA, Berg RL, Linneman JG, Zhao C, McCarty CA, Krauss RM. Characterization of low-density lipoprotein cholesterol-lowering efficacy for atorvastatin in a population-based DNA biorepository. Basic Clin Pharmacol Toxicol. 2008;103(4):354–9.PubMedCrossRefGoogle Scholar
  72. 72.
    •• Wilke RA, Ramsey LB, Johnson SG, et al. The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther. 2012;92(1):112–7. Guidelines incorporating genetic variation in SLCO1B1 to reduce statin related myopathy.PubMedCrossRefGoogle Scholar
  73. 73.
    Rathz DA, Brown KM, Kramer LA, Liggett SB. Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol. 2002;39(2):155–60.PubMedCrossRefGoogle Scholar
  74. 74.
    Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem. 1999;274(18):12670–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Brodde OE. Beta1- and beta2-adrenoceptor polymorphisms and cardiovascular diseases. Fundam Clin Pharmacol. 2008;22(2):107–25.PubMedCrossRefGoogle Scholar
  76. 76.
    Chen L, Meyers D, Javorsky G, et al. Arg389Gly-beta1-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(11):941–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Lobmeyer MT, Gong Y, Terra SG, et al. Synergistic polymorphisms of beta1 and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet Genomics. 2007;17(4):277–82.PubMedCrossRefGoogle Scholar
  78. 78.
    Bristow MR, Murphy GA, Krause-Steinrauf H, et al. An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure. Circ Heart Fail. 2010;3(1):21–8.PubMedCrossRefGoogle Scholar
  79. 79.
    White HL, de Boer RA, Maqbool A, et al. 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):463–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Liu J, Liu ZQ, Yu BN, et al. beta1-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin Pharmacol Ther. 2006;80(1):23–32.PubMedCrossRefGoogle Scholar
  81. 81.
    Karlsson J, Lind L, Hallberg P, 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
  82. 82.
    Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33(32):9414–9.PubMedCrossRefGoogle Scholar
  83. 83.
    de Groote P, Helbecque N, Lamblin N, 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(3):137–42.PubMedCrossRefGoogle Scholar
  84. 84.
    Troncoso R, Moraga F, Chiong M, et al. Gln(27)–>Glubeta(2)-adrenergic receptor polymorphism in heart failure patients: differential clinical and oxidative response to carvedilol. Basic Clin Pharmacol Toxicol. 2009;104(5):374–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Rau T, Wuttke H, Michels LM, et al. Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study. Clin Pharmacol Ther. 2009;85(3):269–72.PubMedCrossRefGoogle Scholar
  86. 86.
    Bijl MJ, Visser LE, van Schaik RH, et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther. 2009;85(1):45–50.PubMedCrossRefGoogle Scholar
  87. 87.
    Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther. 2008;83(5):781–7.PubMedCrossRefGoogle Scholar
  88. 88.
    FDA. Table of pharmacogenomic biomarkers in drug labels. 2012 [http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm236819.htm].
  89. 89.
    Liggett SB, Cresci S, Kelly RJ, et al. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med. 2008;14(5):510–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB. A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem. 2000;275(30):23059–64.PubMedCrossRefGoogle Scholar
  91. 91.
    Kardia SL, Kelly RJ, Keddache MA, et al. Multiple interactions between the alpha 2C- and beta1-adrenergic receptors influence heart failure survival. BMC Med Genet. 2008;9:93.PubMedCrossRefGoogle Scholar
  92. 92.
    Petersen M, Andersen JT, Hjelvang BR, et al. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients. Br J Clin Pharmacol. 2011;71(4):556–65.PubMedCrossRefGoogle Scholar
  93. 93.
    Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51(1):197–205.PubMedGoogle Scholar
  94. 94.
    •• Brugts JJ, Isaacs A, Boersma E, 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. First study to identify genetic determinants influencing ACE-I therapy.PubMedCrossRefGoogle Scholar
  95. 95.
    Harrap SB, Tzourio C, Cambien F, 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
  96. 96.
    Agema WR, Jukema JW, Zwinderman AH, van der Wall EE. A meta-analysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization: evidence for publication bias. Am Heart J. 2002;144(5):760–8.PubMedGoogle Scholar
  97. 97.
    Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013–22.PubMedCrossRefGoogle Scholar
  98. 98.
    • Ramirez AH, Shaffer CM, Delaney JT, et al. Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes. Pharmacogenomics J. 2012. doi: 10.1038/tpj.2012.14. Directed genotyping demonstrate how patients developing TdP frequently have rare mutations in genes known to associate cardiac arrhythmia.Google Scholar
  99. 99.
    •• Kaab S, Crawford DC, Sinner MF, et al. A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes. Circ Cardiovasc Genet. 2012;5(1):91–9. Polymorphism (D85N) in important potassium channel (KCNE1) associated with TdP.PubMedCrossRefGoogle Scholar
  100. 100.
    Relling MV, Klein TE. CPIC: clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther. 2011;89(3):464–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Clinical PharmacologyVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of CardiologyCopenhagen University HospitalGentofteDenmark

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