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Pharmacogenomics and Personalized Medicine: Bridging Genetic Knowledge and Clinical Practice

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PanVascular Medicine

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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.

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Abbreviations

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.

References

  • Abrahams E, Ginsburg GS, Silver M (2005) The personalized medicine coalition: goals and strategies. Am J Pharmacogenomics 5:345–355

    Article  PubMed  Google Scholar 

  • Alda M (2013) Personalized psychiatry: many questions, fewer answers. J Psychiatry Neurosci 38:363–365

    Article  PubMed Central  PubMed  Google Scholar 

  • Amado RG et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634

    Article  CAS  PubMed  Google Scholar 

  • Aral H, Vecchio-Sadus A (2008) Toxicity of lithium to humans and the environment – a literature review. Ecotoxicol Environ Saf 70:349–356

    Article  CAS  PubMed  Google Scholar 

  • 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 23:563–567

    Article  CAS  PubMed  Google Scholar 

  • Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  • Bodin L et al (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106:135–140

    Article  CAS  PubMed  Google Scholar 

  • Brumme ZL et al (2003) Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 17:201–208

    Article  CAS  PubMed  Google Scholar 

  • 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 12:20–27

    Article  PubMed  Google Scholar 

  • 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 25:738–742

    Article  CAS  PubMed  Google Scholar 

  • Davies EC, Green CF, Mottram DR, Pirmohamed M (2007) Adverse drug reactions in hospitals: a narrative review. Curr Drug Saf 2:79–87

    Article  PubMed  Google Scholar 

  • Deverka PA, McLeod HL (2008) Harnessing economic drivers for successful clinical implementation of pharmacogenetic testing. Clin Pharmacol Ther 84:191–193

    Article  CAS  PubMed  Google Scholar 

  • Deverka PA, Vernon J, McLeod HL (2010) Economic opportunities and challenges for pharmacogenomics. Annu Rev Pharmacol Toxicol 50:423–437

    Article  CAS  PubMed  Google Scholar 

  • Dienstmann R, Rodon J, Barretina J, Tabernero J (2013) Genomic medicine frontier in human solid tumors: prospects and challenges. J Clin Oncol 31:1874–1884

    Article  PubMed  Google Scholar 

  • Flowers CR, Veenstra D (2004) The role of cost-effectiveness analysis in the era of pharmacogenomics. Pharmacoeconomics 22:481–493

    Article  PubMed  Google Scholar 

  • Frueh FW, Gurwitz D (2004) From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community. Pharmacogenomics 5:571–579

    Article  PubMed  Google Scholar 

  • Gage BF et al (2008) Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 84:326–331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 40:377–401

    Article  PubMed  Google Scholar 

  • Geisler T et al (2008) CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 9:1251–1259

    Article  CAS  PubMed  Google Scholar 

  • Giacomini KM et al (2007) The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther 81:328–345

    Article  CAS  PubMed  Google Scholar 

  • Ginsburg GS, Willard HF (2009) Genomic and personalized medicine: foundations and applications. Transl Res 154:277–287

    Article  PubMed  Google Scholar 

  • Girnita DM, Burckart G, Zeevi A (2008) Effect of cytokine and pharmacogenomic genetic polymorphisms in transplantation. Curr Opin Immunol 20:614–625

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gladding P, Webster M, Ormiston J, Olsen S, White H (2008) Antiplatelet drug nonresponsiveness. Am Heart J 155:591–599

    Article  CAS  PubMed  Google Scholar 

  • Gurwitz D, Weizman A, Rehavi M (2003) Education: teaching pharmacogenomics to prepare future physicians and researchers for personalized medicine. Trends Pharmacol Sci 24:122–125

    CAS  PubMed  Google Scholar 

  • Haas DW et al (2004) Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18:2391–2400

    CAS  PubMed  Google Scholar 

  • Hodgson K et al (2014) Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol 28:133–141

    Google Scholar 

  • 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 6:27–33

    Article  CAS  PubMed  Google Scholar 

  • 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 9:253–60

    Article  Google Scholar 

  • Hulot JS et al (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247

    Article  CAS  PubMed  Google Scholar 

  • Issa AM (2002) Ethical perspectives on pharmacogenomic profiling in the drug development process. Nat Rev Drug Discov 1:300–308

    Article  CAS  PubMed  Google Scholar 

  • Iyer L et al (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47

    Article  CAS  PubMed  Google Scholar 

  • Jain KK (2004) Role of oncoproteomics in the personalized management of cancer. Expert Rev Proteomics 1:49–55

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Klein TE et al (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764

    Article  CAS  PubMed  Google Scholar 

  • Lee SS, Mudaliar A (2009) Medicine. Racing forward: the Genomics and Personalized Medicine Act. Science 323:342

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lievre A et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995

    Article  CAS  PubMed  Google Scholar 

  • Lievre A et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379

    Article  CAS  PubMed  Google Scholar 

  • 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 8:551–561

    Article  Google Scholar 

  • Mai Y et al (2014) Critical appraisal of the views of healthcare professionals with respect to pharmacogenomics and personalized medicine in Greece. Pers Med 11:15–26

    Google Scholar 

  • Mallal S et al (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358:568–579

    Article  PubMed  Google Scholar 

  • 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 18:2484–2492

    CAS  PubMed  Google Scholar 

  • Mega JL et al (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362

    Article  CAS  PubMed  Google Scholar 

  • Mendelsohn J (2013) Personalizing oncology: perspectives and prospects. J Clin Oncol 31:1904–1911

    Article  CAS  PubMed  Google Scholar 

  • 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 64:803–833

    Article  CAS  PubMed  Google Scholar 

  • Mitropoulos K, Johnson L, Vozikis A, Patrinos GP (2011) Relevance of pharmacogenomics for developing countries in Europe. Drug Metabol Drug Interact 26:143–146

    Article  CAS  PubMed  Google Scholar 

  • Mitropoulos K et al (2012) Institutional profile: Golden Helix Institute of Biomedical Research: interdisciplinary research and educational activities in pharmacogenomics and personalized medicine. Pharmacogenomics 13:387–392

    Article  PubMed  Google Scholar 

  • 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 

  • Mok TS et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957

    Article  CAS  PubMed  Google Scholar 

  • Mrazek DA et al (2009) SLC6A4 variation and citalopram response. Am J Med Genet B Neuropsychiatr Genet 150B:341–351

    Article  CAS  PubMed  Google Scholar 

  • Pacheu-Grau D, Gomez-Duran A, Lopez-Perez MJ, Montoya J, Ruiz-Pesini E (2010) Mitochondrial pharmacogenomics: barcode for antibiotic therapy. Drug Discov Today 15:33–39

    Article  CAS  PubMed  Google Scholar 

  • Patrinos GP (2010) General considerations for integrating pharmacogenomics into mainstream medical practice. Hum Genomics 4:371–374

    Article  PubMed Central  PubMed  Google Scholar 

  • Perlis RH et al (2003) Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry 54:879–883

    Article  CAS  PubMed  Google Scholar 

  • 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 34:2227–2236

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Perlis RH et al (2009b) A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry 166:718–725

    Article  PubMed Central  PubMed  Google Scholar 

  • Picard FJ, Bergeron MG (2002) Rapid molecular theranostics in infectious diseases. Drug Discov Today 7:1092–1101

    Article  CAS  PubMed  Google Scholar 

  • Pierce BL, Ahsan H (2010) Case-only genome-wide interaction study of disease risk, prognosis and treatment. Genet Epidemiol 34:7–15

    PubMed Central  PubMed  Google Scholar 

  • Piquette-Miller M, Grant DM (2007) The art and science of personalized medicine. Clin Pharmacol Ther 81:311–315

    Article  CAS  PubMed  Google Scholar 

  • Pirmohamed M (2006) Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 62:509–511

    Article  PubMed Central  PubMed  Google Scholar 

  • Pirmohamed M et al (2013) A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 369:2294–2303

    Article  CAS  PubMed  Google Scholar 

  • Pollock BG et al (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23:587–590

    Article  CAS  PubMed  Google Scholar 

  • Priest VL et al (2006) Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease. Pharmacoeconomics 24:767–781

    Article  PubMed  Google Scholar 

  • Relling MV et al (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008

    Article  CAS  PubMed  Google Scholar 

  • Reydon TA, Kampourakis K, Patrinos GP (2012) Genetics, genomics and society: the responsibilities of scientists for science communication and education. Pers Med 9:633–643

    Article  CAS  Google Scholar 

  • Robertson JA (2001) Consent and privacy in pharmacogenetic testing. Nat Genet 28:207–209

    Article  CAS  PubMed  Google Scholar 

  • Rosell R et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967

    Article  CAS  PubMed  Google Scholar 

  • Roses AD (2004) Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet 5:645–656

    Article  CAS  PubMed  Google Scholar 

  • Rothstein MA, Epps PG (2001) Ethical and legal implications of pharmacogenomics. Nat Rev Genet 2:228–231

    Article  CAS  PubMed  Google Scholar 

  • 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 25:3238–3245

    Article  CAS  PubMed  Google Scholar 

  • Schalekamp T et al (2007) VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 81:185–193

    Article  CAS  PubMed  Google Scholar 

  • 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 97:296–301

    Article  CAS  PubMed  Google Scholar 

  • Severino G, Del Zompo M (2004) Adverse drug reactions: role of pharmacogenomics. Pharmacol Res 49:363–373

    Article  CAS  PubMed  Google Scholar 

  • Severino G et al (2013) Pharmacogenomics of bipolar disorder. Pharmacogenomics 14:655–674

    Article  CAS  PubMed  Google Scholar 

  • 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 16:462–469

    CAS  PubMed  Google Scholar 

  • 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 235:177–182

    Article  CAS  PubMed  Google Scholar 

  • Smart A, Martin P, Parker M (2004) Tailored medicine: whom will it fit? The ethics of patient and disease stratification. Bioethics 18:322–342

    Article  PubMed  Google Scholar 

  • 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 3:508–511

    Article  CAS  PubMed  Google Scholar 

  • Spear BB, Heath-Chiozzi M, Huff J (2001) Clinical application of pharmacogenetics. Trends Mol Med 7:201–204

    Article  CAS  PubMed  Google Scholar 

  • Squassina A, Pisanu C (2013) Personalized medicine in bipolar disorder: how can we overcome the barriers to clinical translation? Pers Med 10:765–768

    Article  CAS  Google Scholar 

  • Squassina A et al (2010) Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice. Pharmacogenomics 11:1149–1167

    Article  PubMed  Google Scholar 

  • 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 12:1559–1569

    Article  CAS  PubMed  Google Scholar 

  • Tamaoki M, Gushima H, Tsutani K (2007) Awareness survey of parties involved in pharmacogenomics in Japan. Pharmacogenomics 8:275–286

    Article  PubMed  Google Scholar 

  • Tighe SK, Mahon PB, Potash JB (2011) Predictors of lithium response in bipolar disorder. Ther Adv Chronic Dis 2:209–226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tsermpini EE et al (2014) Individualizing clozapine and risperidone treatment for schizophrenia patients. Pharmacogenomics 15:95–110

    Article  CAS  PubMed  Google Scholar 

  • 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 43:789–799

    Article  CAS  PubMed  Google Scholar 

  • Vaszar LT, Cho MK, Raffin TA (2003) Privacy issues in personalized medicine. Pharmacogenomics 4:107–112

    Article  PubMed  Google Scholar 

  • Verhoef TI et al (2013) A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 369:2304–2312

    Article  CAS  PubMed  Google Scholar 

  • 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 15:1–44

    Article  CAS  PubMed  Google Scholar 

  • 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 7:1115–1119

    Article  CAS  PubMed  Google Scholar 

  • Zanardi R et al (2001) Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 50:323–330

    Article  CAS  PubMed  Google Scholar 

Further Readings

  • Arranz MJ, de Leon J (2007) Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 12:707–747

    Article  CAS  PubMed  Google Scholar 

  • 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-specialists

    Google Scholar 

  • 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 specialists

    Google Scholar 

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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.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Alessio Squassina Ph.D.

  2. Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy

    Mirko Manchia M.D., Ph.D.

  3. Department of Pharmacology, Dalhousie University, Halifax, NS, Canada

    Mirko Manchia M.D., Ph.D.

  4. Department of Clinical Chemistry, Faculty of Medicine and Health Sciences, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands

    Christina Mitropoulou MBA

  5. Department of Pharmacy, School of Health Sciences, University of Patras, University Campus Rion GR-265 04, Patras, Greece

    Prof. George P. Patrinos Ph.D. (Professor of Pharmacogenomics)

Authors
  1. Alessio Squassina Ph.D.
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  2. Mirko Manchia M.D., Ph.D.
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  3. Christina Mitropoulou MBA
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  4. Prof. George P. Patrinos Ph.D.
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Corresponding author

Correspondence to George P. Patrinos Ph.D. .

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Editors and Affiliations

  1. Akademisches Lehrkrankenhaus MLU, Bitterfeld-Wolfen, Germany

    Peter Lanzer

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Squassina, A., Manchia, M., Mitropoulou, C., Patrinos, G.P. (2014). Pharmacogenomics and Personalized Medicine: Bridging Genetic Knowledge and Clinical Practice. In: Lanzer, P. (eds) PanVascular Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-37393-0_226-1

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