Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice

Pharmacogenomics

Volumn 11, Issue 8, 2010, Pages 1149-1167

  Squassina, Alessio ^a   Manchia, Mirko ^a,b   Manolopoulos, Vangelis G ^c   Artac, Mehmet ^d   Lappa Manakou, Christina ^e   Karkabouna, Sophia ^e   Mitropoulos, Konstantinos ^e   Zompo, Maria Del ^a   Patrinos, George P ^f  

^a UNIVERSITY OF CAGLIARI   (Italy)

^b DALHOUSIE UNIVERSITY   (Canada)

^c DEMOCRITUS UNIVERSITY OF THRACE MEDICAL SCHOOL   (Greece)

^d SELCUK UNIVERSITY   (Turkey)

^e ERASMUS MEDICAL CENTER   (Netherlands)

^f NONE

Author keywords

adverse drug reaction; cancer; cardiovascular disease; genetic test; infectious disease; personalized medicine; pharmacogenomics; psychiatry

Indexed keywords

ABACAVIR; ACENOCOUMAROL; ANTIDEPRESSANT AGENT; AZATHIOPRINE; CARBAMAZEPINE; CARBOPLATIN; CETUXIMAB; CLOPIDOGREL; CLOZAPINE; COUMARIN DERIVATIVE; EFAVIRENZ; ERLOTINIB; FLUOROURACIL; GEFITINIB; IMATINIB; IRINOTECAN; LAPATINIB; LITHIUM CHLORIDE; MARAVIROC; MERCAPTOPURINE; NEUROLEPTIC AGENT; OXALIPLATIN; PACLITAXEL; PANITUMUMAB; PHENPROCOUMON; TENOFOVIR DISOPROXIL; TIOGUANINE; TRASTUZUMAB; UNINDEXED DRUG; WARFARIN;

ACUTE CORONARY SYNDROME; ACUTE LYMPHOBLASTIC LEUKEMIA; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER SURVIVAL; CARDIOVASCULAR DISEASE; CHRONIC MYELOID LEUKEMIA; CLINICAL PRACTICE; COLORECTAL CANCER; DEPRESSION; DIARRHEA; DRUG HYPERSENSITIVITY; DRUG METABOLISM; ENVIRONMENTAL FACTOR; GASTROINTESTINAL STROMAL TUMOR; GENE MUTATION; GENETIC VARIABILITY; HEALTH CARE COST; HEALTH CARE SYSTEM; HEALTH INSURANCE; HEMOGLOBINOPATHY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFECTION; KIDNEY TUBULE DISORDER; LUNG NON SMALL CELL CANCER; MANIA; MEDICAL EDUCATION; MENTAL DISEASE; MYCOBACTERIUM TUBERCULOSIS; NEUTROPENIA; PERSONALIZED MEDICINE; PHARMACOGENOMICS; PHENOTYPE; PROGNOSIS; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; REVIEW; RNA TRANSLATION; STEVENS JOHNSON SYNDROME; THROMBOEMBOLISM;

CLINICAL MEDICINE; HEALTH KNOWLEDGE, ATTITUDES, PRACTICE; HUMANS; INDIVIDUALIZED MEDICINE; PHARMACOGENETICS;

EID: 77955628006     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/pgs.10.97     Document Type: Review

References (167)

1. Spear BB, Heath-Chiozzi M, Huff J: Clinical application of pharmacogenetics. Trends Mol. Med. 7, 201-204 (2001).
2. Davies EC, Green CF, Mottram DR, Pirmohamed M: Adverse drug reactions in hospitals: a narrative review. Curr. Drug Saf. 2,79-87 (2007).
3. Patrinos GP, Grosveld FG: Pharmacogenomics and therapeutics of hemoglobinopathies. Hemoglobin 32, 229-236 (2008).
4. Severino G, Del Zompo M: Adverse drug reactions: role of pharmacogenomics. Pharmacol. Res. 49, 363-373 (2004).
5. Manolopoulos VG: Pharmacogenomics and adverse drug reactions in diagnostic and clinical practice. Clin. Chem. Lab. Med. 45, 801-814 (2007).
6. Roden DM, Altman RB, Benowitz NL et al.: Pharmacogenomics: challenges and opportunities. Ann. Intern. Med. 145, 749-757 (2006).
7. Giacomini KM, Brett CM, Altman RB et al.: The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin. Pharmacol. Ther. 81, 328-345 (2007).
8. Piquette-Miller M, Grant DM: The art and science of personalized medicine. Clin. Pharmacol. Ther. 81, 311-315 (2007).
9. Delisi C: Meetings that changed the world: Santa Fe 1986: human genome baby-steps. Nature 455, 876-877 (2008).
10. Shin J, Kayser SR, Langaee TY: Pharmacogenetics: from discovery to patient care. Am. J. Health Syst. Pharm. 66, 625-637 (2009).
11. de Koning P, Keirns J: Clinical pharmacology, biomarkers and personalized medicine: education please. Biomark. Med. 3,685-700 (2009).
12. Roses AD: Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat. Rev. Genet. 5, 645-656 (2004).
13. Biomarkers Defnitions Working Group: Biomarkers and surrogate endpoints: preferred defnitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89-95 (2001).
14. Jain KK: Role of oncoproteomics in the personalized management of cancer. Expert. Rev. Proteomics 1(1), 49-55 (2004).
15. Mok TS, Wu YL, Thongprasert S et al.: Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947-957 (2009).
16. Rosell R, Moran T, Queralt C et al.: Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958-967 (2009).
17. Lievre A, Bachet JB, Le Corre D et al.: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66, 3992-3995 (2006).
18. Di Fiore F, Blanchard F, Charbonnier F et al.: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br. J. Cancer 96, 1166-1169 (2007).
19. Lievre A, Bachet JB, Boige V et al.: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 26, 374-379 (2008).
20. Amado RG, Wolf M, Peeters M et al.: Wild-type KRAS is required for panitumumab effcacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626-1634 (2008).
21. Sartore-Bianchi A, Moroni M, Veronese S et al.: Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J. Clin. Oncol. 25, 3238-3245 (2007).
22. Iyer L, Das S, Janisch L et al.: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2, 43-47 (2002).
23. Artac M, Bozcuk H, Pehlivan S et al.: The value of XPD and XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma patients with irinotecan-based regimens. J. Cancer Res. Clin. Oncol. 136, 803-809 (2010).
24. Hoskins JM, Marcuello E, Altes A et al.: Irinotecan pharmacogenetics: infuence of pharmacodynamic genes. Clin. Cancer Res. 14, 1788-1796 (2008).
25. Relling MV, Hancock ML, Rivera GK et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J. Natl Cancer Inst. 91, 2001-2008 (1999).
26. Pirmohamed M: Warfarin: almost 60 years old and still causing problems. Br. J. Clin. Pharmacol. 62, 509-511 (2006).
27. James AH, Britt R P, Raskino CL, Thompson SG: Factors affecting the maintenance dose of warfarin. J. Clin. Pathol. 45, 704-706 (1992).
28. Bodin L, Verstuyft C, Tregouet DA et al.: Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106, 135-140 (2005).
29. Schalekamp T, Brasse BP, Roijers JF et al.: VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin. Pharmacol. Ther. 81, 185-193 (2007).
30. Wadelius M, Chen LY, Lindh JD et al.: The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 113, 784-792 (2009).
31. Stehle S, Kirchheiner J, Lazar A, Fuhr U: Pharmacogenetics of oral anticoagulants: a basis for dose individualization. Clin. Pharmacokinet. 47, 565-594 (2008).
32. Sconce EA, Khan TI, Wynne HA et al.: The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106, 2329-2333 (2005).
33. Gage BF, Eby C, Johnson JA et al.: Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin. Pharmacol. Ther. 84, 326-331 (2008).
34. Klein TE, Altman RB, Eriksson N et al.: Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360, 753-764 (2009).
35. Hillman MA, Wilke RA, Yale SH et al.: A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin. Med. Res. 3, 137-145 (2005).
36. Caraco Y, Blotnick S, Muszkat M: CYP2C9 genotype-guided warfarin prescribing enhances the effcacy and safety of anticoagulation: a prospective randomized controlled study. Clin. Pharmacol. Ther. 83, 460-470 (2008).
37. Anderson JL, Horne BD, Stevens SM et al.: Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116, 2563-2570 (2007).
38. Schwarz UI, Ritchie MD, Bradford Y et al.: Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med. 358, 999-1008 (2008).
39. 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 10, 1687-1695 (2009).
40. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G: Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, S160-S198 (2008).
41. Thomas D, Giugliano RP: Antiplatelet therapy in early management of non-ST-segment elevation acute coronary syndrome: the 2002 and 2007 guidelines from North America and Europe. J. Cardiovasc. Pharmacol. 51, 425-433 (2008).
42. Reaume KT, Regal RE, Dorsch MP: Indications for dual antiplatelet therapy with aspirin and clopidogrel: evidence-based recommendations for use. Ann. Pharmacother. 42, 550-557 (2008).
43. Simon DI, Jozic J: Drug-eluting stents and antiplatelet resistance. Am. J. Cardiol. 102, J29-J37 (2008).
44. Gladding P, Webster M, Ormiston J, Olsen S, White H: Antiplatelet drug nonresponsiveness. Am. Heart J. 155, 591-599 (2008).
45. Gurbel PA, Tantry US: Aspirin and clopidogrel resistance: consideration and management. J. Interv. Cardiol. 19, 439-448 (2006).
46. Geisler T, Schaeffeler E, Dippon J et al.: CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 9(9), 1251-1259 (2008).
47. Chen BL, Zhang W, Li Q et al.: Inhibition of ADP-induced platelet aggregation by clopidogrel is related to CYP2C19 genetic polymorphisms. Clin. Exp. Pharmacol. Physiol 35, 904-908 (2008).
48. Rocca B, Patrono C: Determinants of the interindividual variability in response to antiplatelet drugs. J. Thromb. Haemost. 3, 1597-1602 (2005).
49. 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 108, 2244-2247 (2006).
50. 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 119, 2553-2560 (2009).
51. Mega JL, Close SL, Wiviott SD et al.: Cytochrome P-450 polymorphisms and response to clopidogrel. N. Engl. J. Med. 360, 354-362 (2009).
52. 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. 51, 1925-1934 (2008).
53. 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 121, 512-518 (2010).
54. Giusti B, Gori AM, Marcucci R, Abbate R: Relation of CYP2C19 loss-of-function polymorphism to the occurrence of stent thrombosis. Expert. Opin. Drug Metab. Toxicol. 6(4), 393-407 (2010).
55. 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 373, 309-317 (2009).
56. Ellis KJ, Stouffer GA, McLeod HL, Lee CR: Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. Pharmacogenomics 10(11), 1799-1817 (2009).
57. Sim SC, Risinger C, Dahl ML et al.: A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin. Pharmacol. Ther. 79, 103-113 (2006).
58. Ragia G, Arvanitidis KI, Tavridou A, Manolopoulos VG: Need for reassessment of reported CYP2C19 allele frequencies in various populations in view of CYP2C19*17 discovery: the case of Greece. Pharmacogenomics 10, 43-49 (2009).
59. Arranz MJ, Dawson E, Shaikh S et al.: Cytochrome P4502D6 genotype does not determine response to clozapine. Br. J. Clin. Pharmacol. 39, 417-420 (1995).
60. Riedel M, Schwarz MJ, Strassnig M et al.: Risperidone plasma levels, clinical response and side-effects. Eur. Arch. Psychiatry Clin. Neurosci. 255, 261-268 (2005).
61. de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ: The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J. Clin. Psychiatry 66, 15-27 (2005).
62. Kakihara S, Yoshimura R, Shinkai K et al.: Prediction of response to risperidone treatment with respect to plasma concencentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. Int. Clin. Psychopharmacol. 20, 71-78 (2005).
63. Kirchheiner J, Nickchen K, Bauer M et al.: Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol. Psychiatry 9, 442-473 (2004).
64. Murayama N, Soyama A, Saito Y et al.: Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes. J. Pharmacol. Exp. Ther. 308, 300-306 (2004).
65. Kootstra-Ros JE, Smallegoor W, van der WJ: The cytochrome P450 CYP1A2 genetic polymorphisms *1F and *1D do not affect clozapine clearance in a group of schizophrenic patients. Ann. Clin. Biochem. 42, 216-219 (2005).
66. Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteux G: Polymorphisms in the CYP2D6 gene: association with plasma concentrations of fuoxetine and paroxetine. Ther. Drug Monit. 25, 738-742 (2003).
67. Scordo MG, Spina E, Dahl ML, Gatti G, Perucca E: Infuence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fuoxetine and norfuoxetine. Basic Clin. Pharmacol. Toxicol. 97, 296-301 (2005).
68. Shams ME, Arneth B, Hiemke C et al.: CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J. Clin. Pharm. Ther. 31, 493-502 (2006).
69. Guzey C, Spigset O: Low serum concentrations of paroxetine in CYP2D6 ultrarapid metabolizers. J. Clin. Psychopharmacol. 26, 211-212 (2006).
70. Hinrichs JW, Loovers HM, Scholten B, van der Weide J: Semi-quantitative CYP2D6 gene doses in relation to metabolic ratios of psychotropics. Eur. J. Clin. Pharmacol. 64, 979-986 (2008).
71. Rodriguez-Antona C, Gurwitz D, de Leon J et al.: CYP2D6 genotyping for psychiatric patients treated with risperidone: considerations for cost-effectiveness studies. Pharmacogenomics 10, 685-699 (2009).
72. Bertilsson L, Dahl ML, Sjoqvist F et al.: Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341, 63 (1993).
73. Meyer UA: Pharmacogenetics and adverse drug reactions. Lancet 356, 1667-1671 (2000).
74. Howes OD, Egerton A, Allan V, McGuire P, Stokes P, Kapur S: Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Curr. Pharm. Des 15, 2550-2559 (2009).
75. 3 receptor and neuroleptic drug effects in schizophrenic patients. Schizophr. Res. 49, 223-225 (2001).
76. 3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 124B, 1-5 (2004).
77. 3 genotype association with greater acute positive symptom remission with olanzapine therapy in predominately Caucasian patients with chronic schizophrenia or schizoaffective disorder. Hum. Psychopharmacol. 23, 267-274 (2008).
78. 2 receptor gene. Am. J. Psychiatry 158, 802-804 (2001).
79. Arranz MJ, de Leon J: Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol. Psychiatry 12, 707-747 (2007).
80. Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M: Polymorphism within the promoter of the serotonin transporter gene and antidepressant effcacy of fuvoxamine. Mol. Psychiatry 3, 508-511 (1998).
81. Pollock BG, Ferrell RE, Mulsant BH et al.: Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23, 587-590 (2000).
82. Zanardi R, Serretti A, Rossini D et al.: Factors affecting fuvoxamine antidepressant activity: infuence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol. Psychiatry 50, 323-330 (2001).
83. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ: Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol. Psychiatry 7, 1115-1119 (2002).
84. Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L: 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 (2003).
85. Perlis RH, Mischoulon D, Smoller JW et al.: Serotonin transporter polymorphisms and adverse effects with fuoxetine treatment. Biol. Psychiatry 54, 879-883 (2003).
86. Hong CJ, Chen TJ, Yu YW, Tsai SJ: Response to fuoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J. 6, 27-33 (2006).
87. Mrazek DA, Rush AJ, Biernacka JM et al.: SLC6A4 variation and citalopram response. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 341-351 (2009).
88. Cusin C, Serretti A, Zanardi R et al.: Infuence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int. J. Neuropsychopharmacol. 5, 27-35 (2002).
89. McMahon FJ, Buervenich S, Charney D et al.: Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am. J. Hum. Genet. 78, 804-814 (2006).
90. Kato M, Fukuda T, Wakeno M et al.: Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 115-123 (2009).
91. Uher R, Huezo-Diaz P, Perroud N et al.: Genetic predictors of response to antidepressants in the GENDEP project. Pharmacogenomics J. 9, 225-233 (2009).
92. Kato M, Fukuda T, Wakeno M et al.: Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fuvoxamine effcacy and adverse drug reactions in depressed Japanese patients. Neuropsychobiology 53, 186-195 (2006).
93. Ising M, Lucae S, Binder EB et al.: A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch. Gen. Psychiatry 66, 966-975 (2009).
94. Shyn SI, Shi J, Kraft JB et al.: Novel loci for major depression identifed by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies. Mol. Psychiatry DOI: 10.1038/mp.2009.125 (2009) (Epub ahead of print).
95. Uher R, Perroud N, Ng MY et al.: Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am. J. Psychiatry 167, 555-564 (2010).
96. Aral H, Vecchio-Sadus A: Toxicity of lithium to humans and the environment-a literature review. Ecotoxicol. Environ. Saf. 70, 349-356 (2008).
97. Cruceanu C, Alda M, Turecki G: Lithium: a key to the genetics of bipolar disorder. Genome Med. 1, 79 (2009).
98. Rybakowski JK, Suwalska A, Czerski PM, Dmitrzak-Weglarz M, Leszczynska-Rodziewicz A, Hauser J: Prophylactic effect of lithium in bipolar affective illness may be related to serotonin transporter genotype. Pharmacol. Rep. 57, 124-127 (2005).
99. Serretti A, Lilli R, Mandelli L, Lorenzi C, Smeraldi E: Serotonin transporter gene associated with lithium prophylaxis in mood disorders. Pharmacogenomics J. 1, 71-77 (2001).
100. Serretti A, Malitas PN, Mandelli L et al.: Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders. Pharmacogenomics J. 4, 267-273 (2005).
101. Perlis RH, Smoller JW, Ferreira MA et al.: A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am. J. Psychiatry 166, 718-725 (2009).
102. Schulze TG, Alda M, Adli M et al.: The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology 62, 72-78 (2010).
103. Baquero F: Antibiotic resistance in Spain: what can be done? Task Force of the General Direction for Health Planning of the Spanish Ministry of Health. Clin. Infect. Dis. 23, 819-823 (1996).
104. McCaig LF, Hughes JM: Trends in antimicrobial drug prescribing among offce-based physicians in the United States. JAMA 273, 214-219 (1995).
105. Picard FJ, Bergeron MG: Rapid molecular theranostics in infectious diseases. Drug Discov. Today 7, 1092-1101 (2002).
106. Zhang R, Zhang CT: The impact of comparative genomics on infectious disease research. Microbes Infect. 8, 1613-1622 (2006).
107. Behr MA, Wilson MA, Gill WP et al.: Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284, 1520-1523 (1999).
108. d'Arminio MA, Lepri AC, Rezza G et al.: Insights into the reasons for discontinuation of the frst highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS 14, 499-507 (2000).
109. Mallal S, Phillips E, Carosi G et al.: HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568-579 (2008).
110. Young B, Squires K, Patel P et al.: First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS 22, 1673-1675 (2008).
111. Haas DW, Ribaudo HJ, Kim RB et al.: Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18, 2391-2400 (2004).
112. Brumme ZL, Dong W W, Chan KJ et al.: Infuence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 17, 201-208 (2003).
113. Rodriguez-Novoa S, Labarga P, Soriano V: Pharmacogenetics of tenofovir treatment. Pharmacogenomics 10, 1675-1685 (2009).
114. Chung WH, Hung SI, Hong HS et al.: Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428, 486 (2004).
115. Hung SI, Chung WH, Jee SH et al.: Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet. Genomics 16, 297-306 (2006).
116. Man CB, Kwan P, Baum L et al.: Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 48, 1015-1018 (2007).
117. Sissung TM, English BC, Venzon D, Figg WD, Deeken JF: Clinical pharmacology and pharmacogenetics in a genomics era: the DMET platform. Pharmacogenomics 11, 89-103 (2010).
118. Ruano G, Goethe J W, Caley C et al.: Physiogenomic comparison of weight profles of olanzapine-and risperidone-treated patients. Mol. Psychiatry 12, 474-482 (2007).
119. de Leon J, Correa JC, Ruano G, Windemuth A, Arranz MJ, Diaz FJ: Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels. Schizophr. Res. 98, 40-46 (2008).
120. Arranz MJ, Munro J, Birkett J et al.: Pharmacogenetic prediction of clozapine response. Lancet 355, 1615-1616 (2000).
121. Pace BS, Zein S: Understanding mechanisms of g-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction. Dev. Dyn. 235, 1727-1737 (2006).
122. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ: Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood 89, 1078-1088 (1997).
123. Yavarian M, Karimi M, Bakker E, Harteveld CL, Giordano PC: Response to hydroxyurea treatment in Iranian transfusion-dependent b-thalassemia patients. Haematologica 89, 1172-1178 (2004).
124. Ma Q, Wyszynski DF, Farrell JJ et al.: Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea. Pharmacogenomics J. 7, 386-394 (2007).
125. Scheuner MT, Sieverding P, Shekelle PG: Delivery of genomic medicine for common chronic adult diseases: a systematic review. JAMA 299, 1320-1334 (2008).
126. Gurwitz D, Lunshof JE, Dedoussis G et al.: Pharmacogenomics education: International Society of harmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education. Pharmacogenomics J. 5, 221-225 (2005).
127. Gurwitz D, Weizman A, Rehavi M: Education: teaching pharmacogenomics to prepare future physicians and researchers for personalized medicine. Trends Pharmacol. Sci. 24, 122-125 (2003).
128. Frueh FW, Gurwitz D: From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community. Pharmacogenomics 5, 571-579 (2004).
129. Higgs JE, Andrews J, Gurwitz D, Payne K, Newman W: Pharmacogenetics education in British medical schools. Genomic. Med. 2, 101-105 (2008).
130. Julian-Reynier C, Nippert I, Calefato JM et al.: Genetics in clinical practice: general practitioners' educational priorities in European countries. Genet. Med. 10, 107-113 (2008).
131. Fargher EA, Eddy C, Newman W et al.: Patients' and healthcare professionals' views on pharmacogenetic testing and its future delivery in the NHS. Pharmacogenomics 8, 1511-1519 (2007).
132. Tamaoki M, Gushima H, Tsutani K: Awareness survey of parties involved in pharmacogenomics in Japan. Pharmacogenomics 8, 275-286 (2007).
133. Mrazek M, Koenig B, Skime M et al.: Assessing attitudes about genetic testing as a component of continuing medical education. Acad. Psychiatry 31, 447-451 (2007).
134. Deverka PA, Vernon J, McLeod HL: Economic opportunities and challenges for pharmacogenomics. Annu. Rev. Pharmacol. Toxicol. 50, 423-437 (2010).
135. Perlis RH, Patrick A, Smoller JW, Wang PS: 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 (2009).
136. Carlson JJ, Garrison LP, Ramsey SD, Veenstra DL: 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 (2009).
137. Priest VL, Begg EJ, Gardiner SJ et al.: Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of infammatory bowel disease. Pharmacoeconomics. 24, 767-781 (2006).
138. Ginsburg GS, Willard HF: Genomic and personalized medicine: foundations and applications. Transl. Res. 154, 277-287 (2009).
139. Williams MS: Insurance coverage for pharmacogenomics testing in the USA. Pers. Med. 4, 479-487 (2007).
140. Deverka PA, McLeod HL: Harnessing economic drivers for successful clinical implementation of pharmacogenetic testing. Clin. Pharmacol. Ther. 84, 191-193 (2008).
141. Flowers CR, Veenstra D: The role of cost-effectiveness analysis in the era of pharmacogenomics. Pharmacoeconomics 22, 481-493 (2004).
142. Garrison LP Jr, Carlson RJ, Carlson JJ, Kuszler PC, Meckley LM, Veenstra DL: A review of public policy issues in promoting the development and commercialization of pharmacogenomic applications: challenges and implications. Drug Metab. Rev. 40, 377-401 (2008).
143. Matloff ET, Shappell H, Brierley K, Bernhardt BA, McKinnon W, Peshkin BN: What would you do? Specialists' perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination. J. Clin. Oncol. 18, 2484-2492 (2000).
144. Huizenga CR, Lowstuter K, Banks KC, Lagos VI, Vandergon VO, Weitzel JN: Evolving perspectives on genetic discrimination in health insurance among health care providers. Fam. Cancer 9(2), 253-260 (2009).
145. Robertson JA: Consent and privacy in pharmacogenetic testing. Nat. Genet. 28, 207-209 (2001).
146. Issa AM: Ethical perspectives on pharmacogenomic profling in the drug development process. Nat. Rev. Drug Discov. 1, 300-308 (2002).
147. Morley KI, Hall WD: Using pharmacogenetics and pharmacogenomics in the treatment of psychiatric disorders: some ethical and economic considerations. J. Mol. Med. 82, 21-30 (2004).
148. Rothstein MA, Epps PG: Ethical and legal implications of pharmacogenomics. Nat. Rev. Genet. 2, 228-231 (2001).
149. Godard B, Cardinal G: Ethical implications in genetic counseling and family studies of the epilepsies. Epilepsy Behav. 5, 621-626 (2004).
150. Vaszar LT, Cho MK, Raffn TA: Privacy issues in personalized medicine. Pharmacogenomics 4, 107-112 (2003).
151. Buchanan A, Califano A, Kahn J, McPherson E, Robertson J, Brody B: Pharmacogenetics: ethical issues and policy options. Kennedy. Inst. Ethics J. 12, 1-15 (2002).
152. Smart A, Martin P, Parker M: Tailored medicine: whom will it ft? The ethics of patient and disease stratifcation. Bioethics. 18, 322-342 (2004).
153. Slaughter LM: The Genetic Information Nondiscrimination Act: why your personal genetics are still vulnerable to discrimination. Surg. Clin. North Am. 88, 723-38, vi (2008).
154. Braff JP, Chatterjee B, Hochman M et al.: Patient-tailored medicine, part two: personalized medicine and the legal landscape. J. Health Life Sci. Law 2, 1-43 (2009).
155. Obama B: The Genomics and Personalized Medicine Act of 2006. Clin. Adv. Hematol. Oncol. 5, 39-40 (2007).
156. Dressler LG, Terry SF: How will GINA infuence participation in pharmacogenomics research and clinical testing? Clin. Pharmacol. Ther. 86, 472-475 (2009).
157. Lee SS, Mudaliar A: Medicine. Racing forward: the Genomics and Personalized Medicine Act. Science 323, 342 (2009).
158. van Rijn MJ, van Duijn CM, Slooter AJ: Impact of genetic testing on complex diseases. Eur. J. Epidemiol. 20, 383-388 (2005).
159. Manolio TA, Collins FS, Cox NJ et al.: Finding the missing heritability of complex diseases. Nature 461, 747-753 (2009).
160. Pierce BL, Ahsan H: Case-only genome-wide interaction study of disease risk, prognosis and treatment. Genet. Epidemiol. 34, 7-15 (2010).
161. Pacheu-Grau D, Gomez-Duran A, Lopez-Perez MJ, Montoya J, Ruiz-Pesini E: Mitochondrial pharmacogenomics: barcode for antibiotic therapy. Drug Discov. Today 15, 33-39 (2010).
162. Blanc H, Adams CW, Wallace DC: Different nucleotide changes in the large rRNA gene of the mitochondrial DNA confer chloramphenicol resistance on two human cell lines. Nucleic Acids Res. 9, 5785-5795 (1981).
163. King MP, Attardi G: Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 52, 811-819 (1988).
164. Luca CC, Lam BL, Moraes CT: Erythromycin as a potential precipitating agent in the onset of Leber's hereditary optic neuropathy. Mitochondrion 4, 31-36 (2004).
165. Girnita DM, Burckart G, Zeevi A: Effect of cytokine and pharmacogenomic genetic polymorphisms in transplantation. Curr. Opin. Immunol. 20, 614-625 (2008).
166. Abrahams E, Ginsburg GS, Silver M: The Personalized Medicine Coalition: goals and strategies. Am. J. Pharmacogenomics 5, 345-355 (2005).
167. Koslow SH, Williams LM, Gordon E: Personalized medicine for the brain: a call for action. Mol. Psychiatry 15(3), 229-230 (2010).