Hughes, D. & Andersson, D. I. Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms. Nature Rev. Genet. 16, 459–471 (2015).
Evans, W. E. & Relling, M. V. Moving towards individualized medicine with pharmacogenomics. Nature 429, 464–468 (2004).
A review of pharmacogenomics, from discovery to the clinic.
Alving, A. S., Carson, P. E., Flanagan, C. L. & Ickes, C. E. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 124, 484–485 (1956).
Roll-Hansen, N. The crucial experiment of Wilhelm Johannsen. Biol. Phil. 4, 303–329 (1989).
Motulsky, A. G. Drug reactions enzymes, and biochemical genetics. J. Am. Med. Assoc. 165, 835–837 (1957).
Kalow, W. & Genest, K. A method for the detection of atypical forms of human serum cholinesterase; determination of dibucaine numbers. Can. J. Biochem. Physiol. 35, 339–346 (1957).
Vogel, F. Moderne problem der humangenetik. Ergeb. Inn. Med. U. Kinderheik. 12, 52–125 (1959).
Vesell, E. S. & Page, J. G. Genetic control of drug levels in man: antipyrine. Science 161, 72–73 (1968).
Hughes, H. B., Biehl, J. P., Jones, A. P. & Schmidt, L. H. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am. Rev. Tuberc. 70, 266–273 (1954).
Price Evans, D. A., Manley, K. A. & McKusick, V. A. Genetic control of isoniazid metabolism in man. Br. Med. J. 2, 485–491 (1960).
Blum, M., Demierre, A., Grant, D. M., Heim, M. & Meyer, U. A. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc. Natl Acad. Sci. USA 88, 5237–5241 (1991).
Vatsis, K. P., Martell, K. J. & Weber, W. W. Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc. Natl Acad. Sci. USA 88, 6333–6337 (1991).
Gonzalez, F. J. et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331, 442–446 (1988).
Ingelman-Sundberg, M. Pharmacogenomic biomarkers for prediction of severe adverse drug reactions. N. Engl. J. Med. 358, 637–639 (2008).
Wang, L., McLeod, H. L. & Weinshilboum, R. M. Genomics and drug response. N. Engl. J. Med. 364, 1144–1153 (2011).
Yates, C. R. et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608–614 (1997).
Marshall, E. Preventing toxicity with a gene test. Science 302, 588–590 (2003).
Carr, D. F., Alfirevic, A. & Pirmohamed, M. Pharmacogenomics: Current state-of-the-art. Genes (Basel) 5, 430–443 (2014).
Pirmohamed, M., Kamali, F., Daly, A. K. & Wadelius, M. Oral anticoagulation: a critique of recent advances and controversies. Trends Pharmacol. Sci. 36, 153–163 (2015).
A discussion of how to evaluate the benefits of individualized therapy, and how population differences can complicate this, for warfarin — one of the most important clinically actionable drugs.
Burke, W. in Current Protocols in Human Genetics Unit 9.15, 9.15.1–9.15.7 (John Wiley & Sons, 2009).
Gaedigk, A. Complexities of CYP2D6 gene analysis and interpretation. Int. Rev. Psychiatry 25, 534–553 (2013).
Grosse, S. D. & Khoury, M. J. What is the clinical utility of genetic testing? Genet. Med. 8, 448–450 (2006).
Scott, S. A. Personalizing medicine with clinical pharmacogenetics. Genet. Med. 13, 987–995 (2011).
Chen, Z., Liew, D. & Kwan, P. Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions. Neurology 83, 2077–2084 (2014).
Relling, M. V. & Klein, T. E. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin. Pharmacol. Ther. 89, 464–467 (2011).
Caudle, K. E. et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr. Drug Metab. 15, 209–217 (2014).
Crews, K. R. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin. Pharmacol. Ther. 95, 376–382 (2014).
Mallal, S. et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008).
Martin, M. A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and abacavir dosing: 2014 update. Clin. Pharmacol. Ther. 95, 499–500 (2014).
Province, M. A., Altman, R. B. & Klein, T. E. Interpreting the CYP2D6 results from the International Tamoxifen Pharmacogenetics Consortium. Clin. Pharmacol. Ther. 96, 144–146 (2014).
Ratain, M. J., Nakamura, Y. & Cox, N. J. CYP2D6 genotype and tamoxifen activity: understanding interstudy variability in methodological quality. Clin. Pharmacol. Ther. 94, 185–187 (2013).
Brauch, H. et al. Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J. Clin. Oncol. 31, 176–180 (2013).
Irvin, W. J. Jr et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J. Clin. Oncol. 29, 3232–3239 (2011).
Brauch, H. & Schwab, M. Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer. Br. J. Clin. Pharmacol. 77, 695–703 (2014).
Province, M. A. et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin. Pharmacol. Ther. 95, 216–227 (2014).
Ehmann, F. et al. Pharmacogenomic information in drug labels: European Medicines Agency perspective. Pharmacogenomics J. 15, 201–210 (2015).
Tutton, R. Pharmacogenomic biomarkers in drug labels: what do they tell us? Pharmacogenomics 15, 297–304 (2014).
Ishiguro, A., Yagi, S. & Uyama, Y. Characteristics of pharmacogenomics/biomarker-guided clinical trials for regulatory approval of anti-cancer drugs in Japan. J. Hum. Genet. 58, 313–316 (2013).
Bosma, P. J. et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N. Engl. J. Med. 333, 1171–1175 (1995).
Beutler, E. G6PD deficiency. Blood 84, 3613–3636 (1994).
McCarthy J. J., McLeod, H. L. & Ginsburg, G. S. Genomic medicine: a decade of successes, challenges, and opportunities. Sci. Transl. Med. 5, 189sr4 (2013).
Kinch, M. S., Haynesworth, A., Kinch, S. L. & Hoyer, D. An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039 (2014).
US Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. US Food and Drug Administration http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm (2015).
PharmGKB. CPIC Genes/Drugs. PharmGKB https://www.pharmgkb.org/cpic/pairs (2015).
Dunnenberger, H. M. et al. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu. Rev. Pharmacol. Toxicol. 55, 89–106 (2015).
A detailed discussion of a pre-emptive approach to the clinical implementation of pharmacogenetics that contains quantitative information on the use of medications that are subject to genetic actionability.
Wheeler, H. E., Maitland, M. L., Dolan, M. E., Cox, N. J. & Ratain, M. J. Cancer pharmacogenomics: strategies and challenges. Nature Rev. Genet. 14, 23–34 (2013).
McLeod, H. L. Cancer pharmacogenomics: early promise, but concerted effort needed. Science 339, 1563–1566 (2013).
An analysis of the considerations for use of both somatic and inherited germline genetic lesions in prescription of anticancer drugs.
Look, A. T., Hayes, F. A., Nitschke, R., McWilliams, N. B. & Green, A. A. Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N. Engl. J. Med. 311, 231–235 (1984).
Pui, C. H., Crist, W. M. & Look, A. T. Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia. Blood 76, 1449–1463 (1990).
Senderowicz, A. M. & Pfaff, O. Similarities and differences in the oncology drug approval process between FDA and European Union with emphasis on in vitro companion diagnostics. Clin. Cancer Res. 20, 1445–1452 (2014).
Pignatti, F. et al. Cancer drug development and the evolving regulatory framework for companion diagnostics in the European Union. Clin. Cancer Res. 20, 1458–1468 (2014).
Flockhart, D. A., Skaar, T., Berlin, D. S., Klein, T. E. & Nguyen, A. T. Clinically available pharmacogenomics tests. Clin. Pharmacol. Ther. 86, 109–113 (2009).
Stocco, G. et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin. Pharmacol. Ther. 85, 164–172 (2009).
Yang, S. K. et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genet. 46, 1017–1020 (2014).
Yang, J. J. et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J. Clin. Oncol. 33, 1235–1242 (2015).
Cheng, Q. et al. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Nature Genet. 37, 878–882 (2005).
Bielinski, S. J. et al. Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time—using genomic data to individualize treatment protocol. Mayo Clin. Proc. 89, 25–33 (2014).
Gottesman, O. et al. The CLIPMERGE PGx Program: clinical implementation of personalized medicine through electronic health records and genomics-pharmacogenomics. Clin. Pharmacol. Ther. 94, 214–217 (2013).
Fernandez, C. A. et al. Concordance of DMET plus genotyping results with those of orthogonal genotyping methods. Clin. Pharmacol. Ther. 92, 360–365 (2012).
Johnson, J. A. et al. Implementing personalized medicine: development of a cost-effective customized pharmacogenetics genotyping array. Clin. Pharmacol. Ther. 92, 437–439 (2012).
Oetjens, M. T. et al. Assessment of a pharmacogenomic marker panel in a polypharmacy population identified from electronic medical records. Pharmacogenomics 14, 735–744 (2013).
Buchanan, J., Wordsworth, S. & Schuh, A. Issues surrounding the health economic evaluation of genomic technologies. Pharmacogenomics 14, 1833–1847 (2013).
Schroeder, S. A. & Frist, W. Phasing out fee-for-service payment. N. Engl. J. Med. 368, 2029–2032 (2013).
Levy, K. D. et al. Prerequisites to implementing a pharmacogenomics program in a large health-care system. Clin. Pharmacol. Ther. 96, 307–309 (2014).
Overby, C. L. et al. Physician attitudes toward adopting genome-guided prescribing through clinical decision support. J. Pers. Med. 4, 35–49 (2014).
Crawford, D. C. et al. eMERGEing progress in genomics—the first seven years. Front. Genet. 5, 184 (2014).
Cavallari, L. H. & Nutescu, E. A. Warfarin pharmacogenetics: to genotype or not to genotype, that is the question. Clin. Pharmacol. Ther. 96, 22–24 (2014).
Chan, N. C. et al. Role of phenotypic and genetic testing in managing clopidogrel therapy. Blood 124, 689–699 (2014).
Stanek, E. J. et al. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin. Pharmacol. Ther. 91, 450–458 (2012).
Swen, J. J. et al. Pharmacogenetics: from bench to byte. Clin. Pharmacol. Ther. 83, 781–787 (2008).
Swen, J. J. et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin. Pharmacol. Ther. 89, 662–673 (2011).
A survey of clinically actionable germline genetic variants and affected medications, with basic prescribing advice.
Yeh, P. et al. DNA-mutation inventory to refine and enhance cancer treatment (DIRECT): a catalog of clinically relevant cancer mutations to enable genome-directed anticancer therapy. Clin. Cancer Res. 19, 1894–1901 (2013).
Van Allen, E. M., Wagle, N. & Levy, M. A. Clinical analysis and interpretation of cancer genome data. J. Clin. Oncol. 31, 1825–1833 (2013).
An overview of databases that can be used to match somatic cancer-specific genetic variants with targeted anticancer drugs.
Abrams, J. et al. in 2014 American Society of Clinical Oncology Education Book 71–76 (American Society of Clinical Oncology, 2014).
Agúndez, J. A., Esguevillas, G., Amo, G. & García-Martín, E. Clinical practice guidelines for translating pharmacogenomic knowledge to bedside. Focus on anticancer drugs. Front. Pharmacol. 5, 188 (2014).
Gordon, A. S. et al. Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. Hum. Mol. Genet. 23, 1957–1963 (2014).
Landrum, M. J. et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42, D980–D985 (2014).
Rehm, H. L. et al. ClinGen—the Clinical Genome Resource. N. Engl. J. Med. 372, 2235–2242 (2015).
Whirl-Carrillo, M. et al. Pharmacogenomics knowledge for personalized medicine. Clin. Pharmacol. Ther. 92, 414–417 (2012).
Percha, B., & Altman, R. B. Inferring the semantic relationships of words within an ontology using random indexing: applications to pharmacogenomics. AMIA Annu. Symp. Proc. 2013, 1123–1132 (2013).
Samwald, M. & Freimuth, R. R. Making data on essential pharmacogenes available for every patient everywhere: the Medicine Safety Code initiative. Pharmacogenomics 14, 1529–1531 (2013).
Bell, G. C. et al. Development and use of active clinical decision support for preemptive pharmacogenomics. J. Am. Med. Inform. Assoc. 21, e93–e99 (2014).
Zhu, Q. et al. Harmonization and semantic annotation of data dictionaries from the Pharmacogenomics Research Network: a case study. J. Biomed. Inform. 46, 286–293 (2013).
Overby, C. L. et al. Opportunities for genomic clinical decision support interventions. Genet. Med. 15, 817–823 (2013).
Miñarro-Giménez, J. A., Blagec, K., Boyce, R. D., Adlassnig, K. P. & Samwald, M. An ontology-based, mobile-optimized system for pharmacogenomic decision support at the point-of-care. PLoS ONE 9, e93769 (2014).
Haga, S. B. et al. Survey of genetic counselors and clinical geneticists' use and attitudes toward pharmacogenetic testing. Clin. Genet. 82, 115–120 (2012).
Haga, S. B., Burke, W., Ginsburg, G. S., Mills, R. & Agans, R. Primary care physicians' knowledge of and experience with pharmacogenetic testing. Clin. Genet. 82, 388–394 (2012).
Weber, G. M., Mandl, K. D. & Kohane, I. S. Finding the missing link for big biomedical data. J. Am. Med. Assoc. 311, 2479–2480 (2014).
Hayden, E. C. Geneticists push for global data-sharing. Nature 498, 16–17 (2013).
Prainsack, B. & Vayena, E. Beyond the clinic: 'direct-to-consumer' genomic profiling services and pharmacogenomics. Pharmacogenomics 14, 403–412 (2013).
Caulfield, T. DTC genetic testing: pendulum swings and policy paradoxes. Clin. Genet. 81, 4–6 (2012).
State of Hawaii Department of the Attorney General. State of Hawaii News Release 2014-09 http://ag.hawaii.gov/wp-content/uploads/2014/01/News-Release-2014-09.pdf (2014).
Shuldiner, A. R. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J. Am. Med. Assoc. 302, 849–857 (2009).
Primary findings that showed that CYP2C19 genetic variation affects the effectiveness and bleeding risk from clopidogrel, and led to an FDA 'black box warning' for the drug label.
Mega, J. L. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. J. Am. Med. Assoc. 304, 1821–1830 (2010).
Manolio, T. A. & Green, E. D. Leading the way to genomic medicine. Am. J. Med. Genet. C. Semin. Med. Genet. 166C, 1–7 (2014).
Manolio, T. A., Murray, M. F. & Inter-Society Coordinating Committee for Practitioner Education in Genomics. The growing role of professional societies in educating clinicians in genomics. Genet. Med. 16, 571–572 (2014).
Korf, B. R. et al. Framework for development of physician competencies in genomic medicine: report of the Competencies Working Group of the Inter-Society Coordinating Committee for Physician Education in Genomics. Genet. Med. 16, 804–809 (2014).
Wiener, C. M., Thomas, P. A., Goodspeed, E., Valle, D. & Nichols, D. G. “Genes to society”—the logic and process of the new curriculum for the Johns Hopkins University School of Medicine. Acad. Med. 85, 498–506 (2010).
Manolio, T. A. et al. Global implementation of genomic medicine: we are not alone. Sci. Transl. Med. 7, 290ps13 (2015).
Becquemont, L. et al. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics 12, 113–124 (2011).
Shuldiner, A. R. et al. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: overcoming challenges of real-world implementation. Clin. Pharmacol. Ther. 94, 207–210 (2013).
Pulley, J. M. et al. Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin. Pharmacol. Ther. 92, 87–95 (2012).
A description of the benefits and efficiency of implementing a large and innovative pre-emptive pharmacogenetics programme at a major medical centre.
O'Donnell, P. H. et al. Adoption of a clinical pharmacogenomics implementation program during outpatient care—initial results of the University of Chicago “1,200 Patients Project”. Am. J. Med. Genet. C. Semin. Med. Genet. 166C, 68–75 (2014).
Gottesman, O. et al. The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet. Med. 15, 761–771 (2013).
Rasmussen-Torvik, L. J. et al. Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems. Clin. Pharmacol. Ther. 96, 482–489 (2014).
Rattanavipapong, W., Koopitakkajorn, T., Praditsitthikorn, N., Mahasirimongkol, S. & Teerawattananon, Y. Economic evaluation of HLA-B*15:02 screening for carbamazepine-induced severe adverse drug reactions in Thailand. Epilepsia 54, 1628–1638 (2013).
Toh, D. S. et al. Building pharmacogenetics into a pharmacovigilance program in Singapore: using serious skin rash as a pilot study. Pharmacogenomics J. 14, 316–321 (2014).
Sukasem, C., Puangpetch, A., Medhasi, S. & Tassaneeyakul, W. Pharmacogenomics of drug-induced hypersensitivity reactions: challenges, opportunities and clinical implementation. Asian Pac. J. Allergy Immunol. 32, 111–123 (2014).
Cooper, D. N. et al. Bridging genomics research between developed and developing countries: the Genomic Medicine Alliance. Pers. Med. 11, 615–623 (2014).
Dalabira, E. et al. DruGeVar: an online resource triangulating drugs with genes and genomic biomarkers for clinical pharmacogenomics. Public Health Genomics 17, 265–271 (2014).
Bonifaz-Peña, V. et al. Exploring the distribution of genetic markers of pharmacogenomics relevance in Brazilian and Mexican populations. PLoS ONE 9, e112640 (2014).
Relling, M. V. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin. Pharmacol. Ther. 96, 169–174 (2014).