An Introduction to Pharmacogenomics and Personalized Medicine

  • Alessio Squassina
  • Mirko Manchia
  • Christina Mitropoulou
  • George P. Patrinos
Reference work entry

Abstract

Pharmacogenomics is gradually assuming an integral part in modern medical practice. The exploitation of genomic data to better predict response to medications and avoid adverse drug reactions is becoming a reality in some medical specialties (i.e., personalized medicine). The creation of an informational structured framework of genetic, phenotypic, and environmental factors might provide the health-care system with useful tools that can optimize the effectiveness of specific treatments. In this chapter, we review the most relevant applications of pharmacogenomics, together with an overview of the opportunities and bottlenecks of the implementation of genetic information in personalized medicine and of its full adoption in clinical settings.

Keywords

Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Mutation Personalized Medicine Epidermal Growth Factor Receptor Gene TPMT Activity 
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.

Glossary of Terms

Personalized medicine

The development of tailored treatments based on the integration and implementation of clinical and molecular (genetic, transcriptomic, proteomic, and metabolomic) data.

Pharmacogenomics

The analysis of how genetic variation affects drug response.

Adverse drug reactions

The development of harmful reactions with the use of a specific drug.

Genetic tests

Analysis of DNA in order to detect heritable diseases.

Databases

Structured collection of data.

Economic evaluation in genomic medicine

Evaluation of the impact of genomic medicine, by identifying, measuring, valuating, and then comparing the costs and benefits of two or more alternative treatments and health technologies. Costs are measured in monetary units, and benefits are the outcome of the therapeutic interventions, which leads to the alleviation from side effects, improvement of the quality of life, and extension of life span. Such evaluation would result in making optimal health-care decisions. Some techniques of the economic evaluation are cost-effectiveness analysis and cost-utility analysis.

Cytochromes P450

This class of enzymes constitutes a family of heme-binding monooxygenases. Members of this enzyme family are involved in the metabolism of drugs and in the synthesis and/or metabolism of steroids, cholesterol, vitamin D3, and eicosanoids.

Notes

Acknowledgements

This work was partly supported by the Regional Councillorship of Health, “Regione Autonoma della Sardegna” with a grant dedicated to Drug Information and surveillance projects to AS and MM and by grants from the Golden Helix Foundation (London, UK) to GPP.

References

  1. Abrahams E, Ginsburg GS, Silver M (2005) The personalized medicine coalition: goals and strategies. Am J Pharmacogenomics 5:345–355CrossRefPubMedGoogle Scholar
  2. Alda M (2013) Personalized psychiatry: many questions, fewer answers. J Psychiatry Neurosci 38:363–365CrossRefPubMedPubMedCentralGoogle Scholar
  3. Amado RG et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634CrossRefPubMedGoogle Scholar
  4. Aral H, Vecchio-Sadus A (2008) Toxicity of lithium to humans and the environment – a literature review. Ecotoxicol Environ Saf 70:349–356CrossRefPubMedGoogle Scholar
  5. Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L (2003) 5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study. J Clin Psychopharmacol 23:563–567CrossRefPubMedGoogle Scholar
  6. Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRefGoogle Scholar
  7. Bodin L et al (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106:135–140CrossRefPubMedGoogle Scholar
  8. Brumme ZL et al (2003) Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 17:201–208CrossRefPubMedGoogle Scholar
  9. Carlson JJ, Garrison LP, Ramsey SD, Veenstra DL (2009) The potential clinical and economic outcomes of pharmacogenomic approaches to EGFR-tyrosine kinase inhibitor therapy in non-small-cell lung cancer. Value Health 12:20–27CrossRefPubMedGoogle Scholar
  10. Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteux G (2003) Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit 25:738–742CrossRefPubMedGoogle Scholar
  11. Davies EC, Green CF, Mottram DR, Pirmohamed M (2007) Adverse drug reactions in hospitals: a narrative review. Curr Drug Saf 2:79–87CrossRefPubMedGoogle Scholar
  12. Deverka PA, McLeod HL (2008) Harnessing economic drivers for successful clinical implementation of pharmacogenetic testing. Clin Pharmacol Ther 84:191–193CrossRefPubMedGoogle Scholar
  13. Deverka PA, Vernon J, McLeod HL (2010) Economic opportunities and challenges for pharmacogenomics. Annu Rev Pharmacol Toxicol 50:423–437CrossRefPubMedGoogle Scholar
  14. Dienstmann R, Rodon J, Barretina J, Tabernero J (2013) Genomic medicine frontier in human solid tumors: prospects and challenges. J Clin Oncol 31:1874–1884CrossRefPubMedGoogle Scholar
  15. Flowers CR, Veenstra D (2004) The role of cost-effectiveness analysis in the era of pharmacogenomics. Pharmacoeconomics 22:481–493CrossRefPubMedGoogle Scholar
  16. Frueh FW, Gurwitz D (2004) From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community. Pharmacogenomics 5:571–579CrossRefPubMedGoogle Scholar
  17. Gage BF et al (2008) Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 84:326–331CrossRefPubMedPubMedCentralGoogle Scholar
  18. Garrison LP Jr, Carlson RJ, Carlson JJ, Kuszler PC, Meckley LM, Veenstra DL (2008) A review of public policy issues in promoting the development and commercialization of pharmacogenomic applications: challenges and implications. Drug Metab Rev 40:377–401CrossRefPubMedGoogle Scholar
  19. Geisler T et al (2008) CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 9:1251–1259CrossRefPubMedGoogle Scholar
  20. Giacomini KM et al (2007) The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther 81:328–345CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ginsburg GS, Willard HF (2009) Genomic and personalized medicine: foundations and applications. Transl Res 154:277–287CrossRefPubMedGoogle Scholar
  22. Girnita DM, Burckart G, Zeevi A (2008) Effect of cytokine and pharmacogenomic genetic polymorphisms in transplantation. Curr Opin Immunol 20:614–625CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gladding P, Webster M, Ormiston J, Olsen S, White H (2008) Antiplatelet drug nonresponsiveness. Am Heart J 155:591–599CrossRefPubMedGoogle Scholar
  24. Gurwitz D, Weizman A, Rehavi M (2003) Education: teaching pharmacogenomics to prepare future physicians and researchers for personalized medicine. Trends Pharmacol Sci 24:122–125CrossRefPubMedGoogle Scholar
  25. Haas DW et al (2004) Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18:2391–2400PubMedGoogle Scholar
  26. Hodgson K et al (2014) Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol 28:133–141Google Scholar
  27. Hong CJ, Chen TJ, Yu YW, Tsai SJ (2006) Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J 6:27–33CrossRefPubMedGoogle Scholar
  28. Huizenga CR, Lowstuter K, Banks KC, Lagos VI, Vandergon VO, Weitzel JN (2009) Evolving perspectives on genetic discrimination in health insurance among health care providers. Fam Cancer 9:253–60CrossRefGoogle Scholar
  29. Hulot JS et al (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247CrossRefPubMedGoogle Scholar
  30. Issa AM (2002) Ethical perspectives on pharmacogenomic profiling in the drug development process. Nat Rev Drug Discov 1:300–308CrossRefPubMedGoogle Scholar
  31. Iyer L et al (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47CrossRefPubMedGoogle Scholar
  32. Jain KK (2004) Role of oncoproteomics in the personalized management of cancer. Expert Rev Proteomics 1:49–55CrossRefPubMedGoogle Scholar
  33. Kampourakis K, Mitropoulou C, Vayena E, Borg J, van Schaik RH, Patrinos GP (2014) Next-generation pharmacogenomics and the promise of precision medicine. EMBO Rep (in press)Google Scholar
  34. Klein TE et al (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764CrossRefPubMedGoogle Scholar
  35. Lee SS, Mudaliar A (2009) Medicine. Racing forward: the Genomics and Personalized Medicine Act. Science 323:342CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lievre A et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995CrossRefPubMedGoogle Scholar
  37. Lievre A et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379CrossRefPubMedGoogle Scholar
  38. Mai Y et al (2011) A critical view of the general public’s awareness and physicians’ opinion of the trends and potential pitfalls of genetic testing in Greece. Pers Med 8:551–561CrossRefGoogle Scholar
  39. Mai Y et al (2014) Critical appraisal of the views of healthcare professionals with respect to pharmacogenomics and personalized medicine in Greece. Pers Med 11:15–26Google Scholar
  40. Mallal S et al (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358:568–579CrossRefPubMedGoogle Scholar
  41. Matloff ET, Shappell H, Brierley K, Bernhardt BA, McKinnon W, Peshkin BN (2000) What would you do? Specialists’ perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination. J Clin Oncol 18:2484–2492PubMedGoogle Scholar
  42. Mega JL et al (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362CrossRefPubMedGoogle Scholar
  43. Mendelsohn J (2013) Personalizing oncology: perspectives and prospects. J Clin Oncol 31:1904–1911CrossRefPubMedGoogle Scholar
  44. Michaud V, Bar-Magen T, Turgeon J, Flockhart D, Desta Z, Wainberg MA (2012) The dual role of pharmacogenetics in HIV treatment: mutations and polymorphisms regulating antiretroviral drug resistance and disposition. Pharmacol Rev 64:803–833CrossRefPubMedGoogle Scholar
  45. Mitropoulos K, Johnson L, Vozikis A, Patrinos GP (2011) Relevance of pharmacogenomics for developing countries in Europe. Drug Metabol Drug Interact 26:143–146CrossRefPubMedGoogle Scholar
  46. Mitropoulos K et al (2012) Institutional profile: Golden Helix Institute of Biomedical Research: interdisciplinary research and educational activities in pharmacogenomics and personalized medicine. Pharmacogenomics 13:387–392CrossRefPubMedGoogle Scholar
  47. Mizzi C, Mitropoulou C, Peters B, Drmanac R, van Schaik RH, Borg J, Patrinos GP (2014) Personalized pharmacogenomics profiling using whole genome sequencing. Pharmacogenomics (Submitted)Google Scholar
  48. Mok TS et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957CrossRefPubMedGoogle Scholar
  49. Mrazek DA et al (2009) SLC6A4 variation and citalopram response. Am J Med Genet B Neuropsychiatr Genet 150B:341–351CrossRefPubMedGoogle Scholar
  50. Pacheu-Grau D, Gomez-Duran A, Lopez-Perez MJ, Montoya J, Ruiz-Pesini E (2010) Mitochondrial pharmacogenomics: barcode for antibiotic therapy. Drug Discov Today 15:33–39CrossRefPubMedGoogle Scholar
  51. Patrinos GP (2010) General considerations for integrating pharmacogenomics into mainstream medical practice. Hum Genomics 4:371–374CrossRefPubMedPubMedCentralGoogle Scholar
  52. Perlis RH et al (2003) Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry 54:879–883CrossRefPubMedGoogle Scholar
  53. Perlis RH, Patrick A, Smoller JW, Wang PS (2009a) When is pharmacogenetic testing for antidepressant response ready for the clinic? A cost-effectiveness analysis based on data from the STAR*D study. Neuropsychopharmacology 34:2227–2236CrossRefPubMedPubMedCentralGoogle Scholar
  54. Perlis RH et al (2009b) A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry 166:718–725CrossRefPubMedPubMedCentralGoogle Scholar
  55. Picard FJ, Bergeron MG (2002) Rapid molecular theranostics in infectious diseases. Drug Discov Today 7:1092–1101CrossRefPubMedGoogle Scholar
  56. Pierce BL, Ahsan H (2010) Case-only genome-wide interaction study of disease risk, prognosis and treatment. Genet Epidemiol 34:7–15PubMedPubMedCentralGoogle Scholar
  57. Piquette-Miller M, Grant DM (2007) The art and science of personalized medicine. Clin Pharmacol Ther 81:311–315CrossRefPubMedGoogle Scholar
  58. Pirmohamed M (2006) Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 62:509–511CrossRefPubMedPubMedCentralGoogle Scholar
  59. Pirmohamed M et al (2013) A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 369:2294–2303CrossRefPubMedGoogle Scholar
  60. Pollock BG et al (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23:587–590CrossRefPubMedGoogle Scholar
  61. Priest VL et al (2006) Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease. Pharmacoeconomics 24:767–781CrossRefPubMedGoogle Scholar
  62. Relling MV et al (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008CrossRefPubMedGoogle Scholar
  63. Reydon TA, Kampourakis K, Patrinos GP (2012) Genetics, genomics and society: the responsibilities of scientists for science communication and education. Pers Med 9:633–643CrossRefGoogle Scholar
  64. Robertson JA (2001) Consent and privacy in pharmacogenetic testing. Nat Genet 28:207–209CrossRefPubMedGoogle Scholar
  65. Rosell R et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967CrossRefPubMedGoogle Scholar
  66. Roses AD (2004) Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet 5:645–656CrossRefPubMedGoogle Scholar
  67. Rothstein MA, Epps PG (2001) Ethical and legal implications of pharmacogenomics. Nat Rev Genet 2:228–231CrossRefPubMedGoogle Scholar
  68. Sartore-Bianchi A et al (2007) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25:3238–3245CrossRefPubMedGoogle Scholar
  69. Schalekamp T et al (2007) VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 81:185–193CrossRefPubMedGoogle Scholar
  70. Scordo MG, Spina E, Dahl ML, Gatti G, Perucca E (2005) Influence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fluoxetine and norfluoxetine. Basic Clin Pharmacol Toxicol 97:296–301CrossRefPubMedGoogle Scholar
  71. Severino G, Del Zompo M (2004) Adverse drug reactions: role of pharmacogenomics. Pharmacol Res 49:363–373CrossRefPubMedGoogle Scholar
  72. Severino G et al (2013) Pharmacogenomics of bipolar disorder. Pharmacogenomics 14:655–674CrossRefPubMedGoogle Scholar
  73. Sjogren S, Inganas M, Lindgren A, Holmberg L, Bergh J (1998) Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 16:462–469PubMedGoogle Scholar
  74. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182CrossRefPubMedGoogle Scholar
  75. Smart A, Martin P, Parker M (2004) Tailored medicine: whom will it fit? The ethics of patient and disease stratification. Bioethics 18:322–342CrossRefPubMedGoogle Scholar
  76. Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M (1998) Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 3:508–511CrossRefPubMedGoogle Scholar
  77. Spear BB, Heath-Chiozzi M, Huff J (2001) Clinical application of pharmacogenetics. Trends Mol Med 7:201–204CrossRefPubMedGoogle Scholar
  78. Squassina A, Pisanu C (2013) Personalized medicine in bipolar disorder: how can we overcome the barriers to clinical translation? Pers Med 10:765–768CrossRefGoogle Scholar
  79. Squassina A et al (2010) Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice. Pharmacogenomics 11:1149–1167CrossRefPubMedGoogle Scholar
  80. Squassina A et al (2011) Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics 12:1559–1569CrossRefPubMedGoogle Scholar
  81. Tamaoki M, Gushima H, Tsutani K (2007) Awareness survey of parties involved in pharmacogenomics in Japan. Pharmacogenomics 8:275–286CrossRefPubMedGoogle Scholar
  82. Tighe SK, Mahon PB, Potash JB (2011) Predictors of lithium response in bipolar disorder. Ther Adv Chronic Dis 2:209–226CrossRefPubMedPubMedCentralGoogle Scholar
  83. Tsermpini EE et al (2014) Individualizing clozapine and risperidone treatment for schizophrenia patients. Pharmacogenomics 15:95–110CrossRefPubMedGoogle Scholar
  84. Uher R, Mantere O, Suominen K, Isometsa E (2013) Typology of clinical course in bipolar disorder based on 18-month naturalistic follow-up. Psychol Med 43:789–799CrossRefPubMedGoogle Scholar
  85. Vaszar LT, Cho MK, Raffin TA (2003) Privacy issues in personalized medicine. Pharmacogenomics 4:107–112CrossRefPubMedGoogle Scholar
  86. Verhoef TI et al (2013) A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 369:2304–2312CrossRefPubMedGoogle Scholar
  87. Yatham LN et al (2013) Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 15:1–44CrossRefPubMedGoogle Scholar
  88. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ (2002) Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 7:1115–1119CrossRefPubMedGoogle Scholar
  89. Zanardi R et al (2001) Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 50:323–330CrossRefPubMedGoogle Scholar

Further Reading

  1. Arranz MJ, de Leon J (2007) Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 12:707–747CrossRefPubMedGoogle Scholar
  2. Collins FS (2011) The language of life: DNA and the revolution of personalized medicine. Harper Perrenial, New York, Accessible text serves as useful general introduction into the topic; comfortable reading for non-specialistsGoogle Scholar
  3. Ruano G, Bronzino JD, Peterson DR (2014) Personalized medicine: principles and practices. CRC Press, Boca Raton (preprint); Comprehensive multi-author comprehensive review of the state of the art practice of personalized medicine for specialistsGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Alessio Squassina
    • 1
  • Mirko Manchia
    • 2
    • 3
  • Christina Mitropoulou
    • 4
  • George P. Patrinos
    • 5
  1. 1.Department of Biomedical SciencesUniversity of CagliariCagliariItaly
  2. 2.Department of Public Health, Clinical and Molecular MedicineUniversity of CagliariCagliariItaly
  3. 3.Department of PharmacologyDalhousie UniversityHalifaxCanada
  4. 4.Department of Clinical Chemistry, Faculty of Medicine and Health SciencesErasmus University Medical Center RotterdamRotterdamThe Netherlands
  5. 5.Department of Pharmacy, School of Health SciencesUniversity of PatrasPatrasGreece

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