Pharmacogenomics pp 3-22

Part of the Methods in Molecular Biology book series (MIMB, volume 1015)

Pharmacogenomics: Historical Perspective and Current Status

  • Rosane Charlab
  • Lei Zhang


Pharmacogenomics and its predecessor pharmacogenetics study the contribution of genetic factors to the interindividual variability in drug efficacy and safety. One of the major goals of pharmacogenomics is to tailor drugs to individuals based on their genetic makeup and molecular profile. From early findings in the 1950s uncovering inherited deficiencies in drug metabolism that explained drug-related adverse events, to nowadays genome-wide approaches assessing genetic variation in multiple genes, pharmacogenomics has come a long way. The evolution of pharmacogenomics has paralleled the evolution of genotyping technologies, the completion of the human genome sequencing and the HapMap project. Despite these advances, the implementation of pharmacogenomics in clinical practice has yet been limited. Here we present an overview of the history and current applications of pharmacogenomics in patient selection, dosing, and drug development with illustrative examples of these categories. Some of the challenges in the field and future perspectives are also presented.

Key words

Pharmacogenetics Pharmacogenomics Pharmacokinetics Pharmacodynamics Polymorphism Adverse event Targeted therapy Drug metabolizing enzyme Drug transporter 


  1. 1.
    Offit K (2011) Personalized medicine: new genomics, old lessons. Hum Genet 130(1): 3–14PubMedCrossRefGoogle Scholar
  2. 2.
    Weinshilboum R, Wang L (2004) Pharmacogenomics: bench to bedside. Nat Rev Drug Discov 3(9):739–748PubMedCrossRefGoogle Scholar
  3. 3.
    Kalow W et al (1998) Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics 8(4):283–289PubMedCrossRefGoogle Scholar
  4. 4.
    Evans WE, McLeod HL (2003) Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 348(6):538–549PubMedCrossRefGoogle Scholar
  5. 5.
    Roden DM et al (2006) Pharmacogenomics: challenges and opportunities. Ann Intern Med 145(10):749–757PubMedCrossRefGoogle Scholar
  6. 6.
    Camilleri M, Saito YA (2008) Pharmacogenomics in gastrointestinal disorders. Methods Mol Biol 448:395–412PubMedCrossRefGoogle Scholar
  7. 7.
    Kirk RJ et al (2008) Implications of pharmacogenomics for drug development. Exp Biol Med (Maywood) 233(12):1484–1497CrossRefGoogle Scholar
  8. 8.
    McLeod HL, Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41:101–121PubMedCrossRefGoogle Scholar
  9. 9.
    Watters JW, McLeod HL (2003) Cancer pharmacogenomics: current and future applications. Biochim Biophys Acta 1603(2):99–111PubMedGoogle Scholar
  10. 10.
    Hudson KL (2011) Genomics, health care, and society. N Engl J Med 365(11): 1033–1041PubMedCrossRefGoogle Scholar
  11. 11.
    Snyder LH (1932) Studies in human inheritance. IX. The inheritance of taste deficiency in man. Ohio J Sci 32:436–468Google Scholar
  12. 12.
    Kim UK et al (2003) Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science 299(5610):1221–1225PubMedCrossRefGoogle Scholar
  13. 13.
    Motulsky AG (1957) Drug reactions enzymes, and biochemical genetics. J Am Med Assoc 165(7):835–837PubMedCrossRefGoogle Scholar
  14. 14.
    Vogel F (1959) Moderne probleme der humangenetik. Ergebn Inn Med Kinderheilkd 12:52–125CrossRefGoogle Scholar
  15. 15.
    Nebert DW et al (2008) From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metab Rev 40(2):187–224PubMedCrossRefGoogle Scholar
  16. 16.
    Ma Q, Lu AY (2011) Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev 63(2):437–459PubMedCrossRefGoogle Scholar
  17. 17.
    Gonzalez FJ et al (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331(6155):442–446PubMedCrossRefGoogle Scholar
  18. 18.
    Blum M et al (1990) Human arylamine N-acetyltransferase genes - isolation, chromosomal localization, and functional expression. DNA Cell Biol 9(3):193–203PubMedCrossRefGoogle Scholar
  19. 19.
    Krynetski EY et al (1995) A single-point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA 92(4):949–953PubMedCrossRefGoogle Scholar
  20. 20.
    Vesell ES (1989) Pharmacogenetic perspectives gained from twin and family studies. Pharmacol Ther 41(3):535–552PubMedCrossRefGoogle Scholar
  21. 21.
    Shin J et al (2009) Pharmacogenetics: from discovery to patient care. Am J Health Syst Pharm 66(7):625–637PubMedCrossRefGoogle Scholar
  22. 22.
    Roden DM et al (2011) Pharmacogenomics: the genetics of variable drug responses. Circulation 123(15):1661–1670PubMedCrossRefGoogle Scholar
  23. 23.
    Evans WE, Relling MV (1999) Relling, Pharmacogenomics: translating functional genomics into rational therapeutics. Science, 286(5439):487–491PubMedCrossRefGoogle Scholar
  24. 24.
    Belle DJ, Singh H (2008) Genetic factors in drug metabolism. Am Fam Physician 77(11): 1553–1560PubMedGoogle Scholar
  25. 25.
    Gaedigk A et al (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83(2):234–242PubMedCrossRefGoogle Scholar
  26. 26.
    Desta Z et al (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41(12):913–958PubMedCrossRefGoogle Scholar
  27. 27.
    Mini E, Nobili S (2009) Pharmacogenetics: implementing personalized medicine. Clin Cases Miner Bone Metab 6(1):17–24PubMedGoogle Scholar
  28. 28.
    Venter JC et al (2001) The sequence of the human genome. Science 291(5507): 1304–1351PubMedCrossRefGoogle Scholar
  29. 29.
    Lander ES et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921PubMedCrossRefGoogle Scholar
  30. 30.
    den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109(1): 121–124CrossRefGoogle Scholar
  31. 31.
    Kacevska M et al (2011) Perspectives on epigenetics and its relevance to adverse drug reactions. Clin Pharmacol Ther 89(6): 902–907PubMedCrossRefGoogle Scholar
  32. 32.
    O’Donnell PH, Dolan ME (2009) Cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy. Clin Cancer Res 15(15):4806–4814PubMedCrossRefGoogle Scholar
  33. 33.
    Lee W et al (2005) Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. Oncologist 10(2):104–111PubMedCrossRefGoogle Scholar
  34. 34.
    Judson R et al (2000) The predictive power of haplotypes in clinical response. Pharmacogenomics 1(1):15–26PubMedCrossRefGoogle Scholar
  35. 35.
    Fujiwara Y, Minami H (2010) An overview of the recent progress in irinotecan pharmacogenetics. Pharmacogenomics 11(3):391–406PubMedCrossRefGoogle Scholar
  36. 36.
    Becquemont L (2009) Pharmacogenomics of adverse drug reactions: practical applications and perspectives. Pharmacogenomics 10(6): 961–969PubMedCrossRefGoogle Scholar
  37. 37.
    Wu X et al (2009) Strategies to identify pharmacogenomic biomarkers: candidate gene, pathway-based, and genome-wide approaches. In: Innocenti F (ed) Genomics and pharmacogenomics in anticancer drug development and clinical response. Humana Press, Totowa NJ, pp 353–370Google Scholar
  38. 38.
    Feero WG et al (2010) Genomic medicine—an updated primer. N Engl J Med 362(21):2001–2011PubMedCrossRefGoogle Scholar
  39. 39.
    Metzker ML (2010) Sequencing technologies—the next generation. Nat Rev Genet 11(1):31–46PubMedCrossRefGoogle Scholar
  40. 40.
    Wilke RA et al (2007) Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6(11):904–916PubMedCrossRefGoogle Scholar
  41. 41.
    Andrade RJ et al (2009) Drug-induced liver injury: insights from genetic studies. Pharmacogenomics 10(9):1467–1487PubMedCrossRefGoogle Scholar
  42. 42.
    Huang YS (2010) Tailored drug therapy for mitigating drug-induced liver injury: is this the era of genetic screening? Pers Med 7(1):5–8CrossRefGoogle Scholar
  43. 43.
    Wang L et al (2011) Genomics and drug response. N Engl J Med 364(12):1144–1153PubMedCrossRefGoogle Scholar
  44. 44.
    Daly AK et al (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41(7):816–819PubMedCrossRefGoogle Scholar
  45. 45.
    Kindmark A et al (2008) Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 8(3):186–195PubMedCrossRefGoogle Scholar
  46. 46.
    Singer JB et al (2010) A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 42(8):711–714PubMedCrossRefGoogle Scholar
  47. 47.
    Tujios S, Fontana RJ (2011) Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol 8(4): 202–211PubMedCrossRefGoogle Scholar
  48. 48.
    Pirmohamed M (2010) Pharmacogenetics of idiosyncratic adverse drug reactions. Handb Exp Pharmacol 196:477–491PubMedCrossRefGoogle Scholar
  49. 49.
    Becquemont L (2010) HLA: a pharmacogenomics success story. Pharmacogenomics 11(3):277–281PubMedCrossRefGoogle Scholar
  50. 50.
    Mallal S et al (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358(6):568–579PubMedCrossRefGoogle Scholar
  51. 51.
    Hung SI et al (2006) Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 16(4):297–306PubMedCrossRefGoogle Scholar
  52. 52.
  53. 53.
    McCormack M et al (2011) HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 364(12):1134–1143PubMedCrossRefGoogle Scholar
  54. 54.
    Ozeki T et al (2011) Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet 20(5):1034–1041PubMedCrossRefGoogle Scholar
  55. 55.
    Somkrua R et al (2011) Association of HLA-B*5801 allele and Allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Med Genet 12(1):118PubMedCrossRefGoogle Scholar
  56. 56.
    Niemi M (2010) Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 87(1):130–133PubMedCrossRefGoogle Scholar
  57. 57.
    Link E et al (2008) SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 359(8):789–799PubMedCrossRefGoogle Scholar
  58. 58.
    Walko CM, McLeod H (2009) Pharmacogenomic progress in individualized dosing of key drugs for cancer patients. Nat Clin Pract Oncol 6(3):153–162PubMedCrossRefGoogle Scholar
  59. 59.
    Innocenti F, Ratain MJ (2006) Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping. Pharmacogenomics 7(8):1211–1221PubMedCrossRefGoogle Scholar
  60. 60.
    Wilke RA, Dolan ME (2011) Genetics and variable drug response. JAMA 306(3):306–307PubMedCrossRefGoogle Scholar
  61. 61.
    Carlquist JF, Anderson JL (2011) Pharmacogenetic mechanisms underlying unanticipated drug responses. Discov Med 11(60):469–478PubMedGoogle Scholar
  62. 62.
    Lovly CM, Carbone DP (2011) Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol 8(2):68–70PubMedCrossRefGoogle Scholar
  63. 63.
    Biankin AV, Hudson TJ (2011) Somatic variation and cancer: therapies lost in the mix. Hum Genet 130(1):79–91PubMedCrossRefGoogle Scholar
  64. 64.
    Chapman PB et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26): 2507–2516PubMedCrossRefGoogle Scholar
  65. 65.
    Shaw AT et al (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12(11):1004–1012PubMedCrossRefGoogle Scholar
  66. 66.
    Hutchinson L (2010) Targeted therapies: activated PI3K/AKT confers resistance to trastuzumab but not lapatinib. Nat Rev Clin Oncol 7(8):424PubMedCrossRefGoogle Scholar
  67. 67.
    Ellis LM, Hicklin DJ (2009) Resistance to targeted therapies: refining anticancer therapy in the era of molecular oncology. Clin Cancer Res 15(24):7471–7478PubMedCrossRefGoogle Scholar
  68. 68.
    PLAVIX (Clopidogrel) Labeling [Online]. Accessed 28 Aug
  69. 69.
    Mega JL et al (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360(4):354–362PubMedCrossRefGoogle Scholar
  70. 70.
    Mega JL et al (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304(16):1821–1830PubMedCrossRefGoogle Scholar
  71. 71.
    Scott SA et al (2011) Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and Clopidogrel therapy. Clin Pharmacol Ther 90(2):328–332PubMedCrossRefGoogle Scholar
  72. 72.
    Daly AK, King BP (2003) Pharmacogenetics of oral anticoagulants. Pharmacogenetics 13(5):247–252PubMedCrossRefGoogle Scholar
  73. 73.
    Kim MJ et al (2009) A regulatory science perspective on warfarin therapy: a pharmacogenetic opportunity. J Clin Pharmacol 49(2):138–146PubMedCrossRefGoogle Scholar
  74. 74.
    Scordo MG et al (2002) Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 72(6):702–710PubMedCrossRefGoogle Scholar
  75. 75.
    Sconce EA et al (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106(7):2329–2333PubMedCrossRefGoogle Scholar
  76. 76.
    Marsh S et al (2006) Population variation in VKORC1 haplotype structure. J Thromb Haemost 4(2):473–474PubMedCrossRefGoogle Scholar
  77. 77.
    Yuan HY et al (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 14(13):1745–1751PubMedCrossRefGoogle Scholar
  78. 78.
    Gage BF, Lesko LJ (2008) Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 25(1):45–51PubMedCrossRefGoogle Scholar
  79. 79.
    Caraco Y et al (2008) CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 83(3):460–470PubMedCrossRefGoogle Scholar
  80. 80.
    Gage BF et al (2008) Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 84(3): 326–331PubMedCrossRefGoogle Scholar
  81. 81.
    Lenzini P et al (2010) Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther 87(5):572–578PubMedCrossRefGoogle Scholar
  82. 82.
    COUMADIN (Warfarin) prescribing information. [Online]. Accessed 28 Aug
  83. 83.
    Tetrabenazine Clinical Pharmacology Review. [Online]. Accessed 28 Aug
  84. 84.
    XENAZINE (Tetrabenazine) Labeling [Online]. Accessed 28 Aug
  85. 85.
    Stingl Kirchheiner JC, Brockmoller J (2011) Why, when, and how should pharmacogenetics be applied in clinical studies? Current and future approaches to study designs. Clin Pharmacol Ther 89(2):198–209PubMedCrossRefGoogle Scholar
  86. 86.
    Zineh I, Pacanowski MA (2011) Pharmacogenomics in the assessment of therapeutic risks versus benefits: inside the United states food and drug administration. Pharmacotherapy 31(8):729–735PubMedCrossRefGoogle Scholar
  87. 87.
    Diamandis M et al (2010) Personalized medicine: marking a new epoch in cancer patient management. Mol Cancer Res 8(9):1175–1187PubMedCrossRefGoogle Scholar
  88. 88.
    Houle D et al (2010) Phenomics: the next challenge. Nat Rev Genet 11(12):855–866PubMedCrossRefGoogle Scholar
  89. 89.
    Pirmohamed M et al (2011) The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions. Clin Pharmacol Ther 89(6): 784–785PubMedCrossRefGoogle Scholar
  90. 90.
    Lanktree MB et al (2010) Phenomics: expanding the role of clinical evaluation in genomic studies. J Investig Med 58(5): 700–706PubMedGoogle Scholar
  91. 91.
    Tracy RP (2008) ‘Deep phenotyping’: characterizing populations in the era of genomics and systems biology. Curr Opin Lipidol 19(2):151–157PubMedCrossRefGoogle Scholar
  92. 92.
    Carson PE et al (1956) Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 124(3220):484–485PubMedCrossRefGoogle Scholar
  93. 93.
    Kalow W (1956) Familial incidence of low pseudocholinesterase level. Lancet 271:576–577CrossRefGoogle Scholar
  94. 94.
    Harris HW et al (1958) Comparison of isoniazid concentrations in the blood of people of Japanese and European descent; therapeutic and genetic implications. Am Rev Tuberc 78(6):944–948PubMedGoogle Scholar
  95. 95.
    Evans DA et al (1960) Genetic control of isoniazid metabolism in man. Br Med J 2(5197):485–491PubMedCrossRefGoogle Scholar
  96. 96.
    Mahgoub A et al (1977) Polymorphic hydroxylation of Debrisoquine in man. Lancet 2(8038):584–586PubMedCrossRefGoogle Scholar
  97. 97.
    Eichelbaum M et al (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 16(3):183–187PubMedCrossRefGoogle Scholar
  98. 98.
    Weinshilboum RM, Sladek SL (1980) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32(5):651–662PubMedGoogle Scholar
  99. 99.
    Ge D et al (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461(7262):399–401PubMedCrossRefGoogle Scholar
  100. 100.
    Eichler HG et al (2011) Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat Rev Drug Discov 10(7):495–506PubMedCrossRefGoogle Scholar
  101. 101.
    Bertilsson L et al (2002) Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 53(2):111–122PubMedCrossRefGoogle Scholar
  102. 102.
    Janne PA et al (2009) Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 8(9): 709–723PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Rosane Charlab
    • 1
  • Lei Zhang
    • 1
  1. 1.Office of Clinical Pharmacology, Office of Translational SciencesCenter for Drug Evaluation and Research, United States Food and Drug AdministrationSilver SpringUSA

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