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1Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Germany; 2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Correspondence: I Cascorbi (cascorbi@pharmakologie.uni-kiel.de)

doi:10.1038/mt.2013.235

Progress in Pharmacogenomics: Bridging the Gap From Research to PracticeI Cascorbi1 and R Tyndale2

Genetic information is increasingly used to optimize clinical treatment of patients, but obstacles remain to practical implementation as well as challenges to our understanding of genetic variation in drug response. These areas that particularly require research attention include gene–environment interactions, the consequences of genetic variation, and the impact of epigenetics on gene expression and function. In this issue of Clinical Pharmacology & Therapeutics focused on pharmacogenetics, we discuss some of the recent advances in understanding from a variety of viewpoints.

This is an exciting decade for applying the science of genetic variation in drug response to clinical translation. Implementation of pharmacogenetics has begun in earnest; numerous clinical facilities are utilizing genetic information to guide, or personalize, medical decisions; and many are initiating prospective genotyping of patients. As the evidence mounts for those gene–drug combinations that can optimize treatment, specific guidelines are being published, for example, those in CPT by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenetics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (http://www.pharmgkb.org).1 Many of the numerous obstacles that have been identified during the process of translation to the clinic must be overcome in the quest to use genetic information to guide

treatment choices.2 The advantages of using genetic information are numerous, but the challenges are also plentiful, including the need to further develop our understanding of other sources of variation in gene expression regulation and epigenetic influences, some of which are described below in the context of pharmacogenetics.

Understanding the molecular background of drug metabolismInitially in the field of pharmacogenetics, it was thought that modulation of pharmacokinetics by genetic variants in single genes would be the major factor contributing to interindividual variability of drug response;3 in some cases this remains true. However, additional factors that contribute to the functional activity of drug-metabolizing enzymes and membrane transporters continue to

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implementation into clinical practice. The pharmacogenetics of warfarin may be one of the best and most discussed examples—variants in only two genes contribute to up to 50% of interindividual variability of drug response, as determined by international normalized ratio (INR) measurement. Turner and Pirmohamed7 and Perera et al.8 describe the evidence for CYP2C9 and VKORCI genotyping in determining warfarin starting-dose requirements; both views were outlined knowing that large studies on this topic were either just published or about to be published. Indeed, Pirmohamed and colleagues led a recently published European study that confirmed that pharmacogenetics-guided dosing shortens the time to reach therapeutic INR by eight days and results in a higher percentage of subjects remaining in the therapeutic window.9 In addition, there were significantly fewer incidents of excessive anticoagulation (INR ≥ 4.0) in the genotype-guided treatment group, suggesting that pharmacogenetics-guided dosing may indeed increase the safety and accuracy of warfarin therapy. Long-term data on the overall outcome, such as the avoidance of thromboembolic events such as stroke, are not yet available from this study. However, the same issue of the New England Journal of Medicine reported a similar US study on pharmacogenetics-guided warfarin dosing that did not find evidence of improvement using a genotype-based algorithm.10

The discrepancy between the outcomes of these two new, large clinical trials of genotype-guided warfarin dosing requires clarification, and may in the meantime dampen enthusiasm for the application of pharmacogenetics to anticoagulation treatment. It should be kept in mind that both studies were based on mathematical algorithms that considered only two single-nucleotide polymorphisms (SNPs)

be identified. Additional variability may involve newly identified functionally significant variants, for example, the recently identified CYP3A4*22, which causes 20% decreased activity in the important drug metabolizing cytochrome P450 enzyme4. These novel variants are even more likely to be found in non-Caucasian populations in whom less sequencing has been performed, especially phenotype-guided sequencing. Other sources of variability include regulation by epigenetic factors or nuclear receptors that can significantly alter gene function. Zanger et al.5 provide an excellent summary of the impact of such static and dynamic factors on cytochrome P450 enzymes. These observations suggest the need to consider genomic, epigenomic, and nongenomic biomarkers to improve modeling of drug response so as to develop individualized treatment strategies.

OncologyIndividualized therapy using prognostic genetic markers has been well established in modern clinical oncology. For example, detection of somatic mutations in tumor tissue may be decisive for the selection of tyrosine kinase or transcription factor inhibitors as treatment strategies.6 The progress made in increasing our understanding of the molecular background of different malignancies, enabling stratified therapeutic options, is clearly due to the enormous technical advances of molecular biological techniques and ever-increasing bioinformatics knowledge.

Cardiovascular diseasesProgress is also occurring in medical indications other than oncology. Non-oncological pharmacogenetic markers, albeit a limited number, have an impact and are advancing toward

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for instance, the association between CYP3A5 genotype and tacrolimus dose requirement is strong, as consistently shown in numerous studies.16 In daily practice, however, the unexpectedly low tacrolimus trough levels often occurring in patients expressing CYP3A5 could be rapidly corrected by elevating the dosage of the immunosuppressant. Likewise, the pharmacokinetics of mycophenolate mofetil is subject to polymorphic pharmacokinetics, whereas for cyclosporine no genetic variants have thus far been identified that are clearly associated with patients’ plasma drug levels.17 It can be concluded that for all three major immunosuppressants there is little evidence so far that the application of pharmacogenetics could improve clinical outcome by lowering nephrotoxicity and the risk of transplant rejection.

Clinical psychiatryIn their Translation piece, Crettol et al. emphasize the role of gene regulation and drug interactions contributing to interindividual differences in the pharmacokinetics/pharmacodynamics (PK/PD) of psychotropic drugs.18 Although a number of drugs whose effects are subject to genetic variation in PK/PD are used in clinical psychiatry, pharmacogenetics is not yet routinely applied. These drugs would benefit from systems-biological analyses of the PK/PD studies, including data from modern technologies such as next-generation sequencing, as it is increasingly clear that variants in other genes may be of additional or even greater importance. The complexity of disease and treatment response in mental illness, as well as in other illnesses involving the brain, provides further motivation to examine the utility of dynamic molecular biomarkers to better understand variation in drug response.

in CYP2C9 and one variant in VKORC1 (ref. 11). The highly significant association of these traits with warfarin response was confirmed by a genome-wide association (GWAS) analysis excluding all other SNPs except CYP4F2.12 Of note, in African Americans, conventional therapy may be superior to pharmacogenetics-guided therapy.10 In fact, in their Macroscopy in this issue,8 Perera et al. emphasize that application of genotype-guided warfarin dosing in minority populations may require consideration of further genetic traits, as GWAS analysis in African Americans revealed an SNP on chromosome 10 near CYP2C18 associated with warfarin dose requirements.13

The paper by Turner and Pirmohamed7 highlights additional aspects of drug safety in cardiovascular drug treatment. For example, drug-induced QT elongation is a major clinical concern. Amiodarone, a major antiarrhythmic drug, bears the risk of evoking torsade-de-point arrhythmias, a risk that is significantly increased in carriers of common variants in the nitric oxide synthase 1 adapter protein.14 The authors propose that an increasing understanding of the molecular background and subsequent novel differentiation of cardiovascular diseases may reveal many more currently unknown genetic and, in particular, epigenetic factors. The introduction of such biomarkers into clinical practice, however, requires clearer definitions of the clinical phenotype, advanced molecular diagnostic tools, and considerable progress in bioinformatics.

Transplantation medicineIn the immunosuppressant therapy of solid-organ transplants, “Pharmacogenetics has not yet reached the transplant clinic,” as stated by van Gelder et al. in their Practice piece.15 On first glance, this seems surprising because,

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provision of pharmacogenetics instruction was poor or inadequate. She points to the successful implementation of genomics in the treatment of both adult and pediatric cancers as an example of its promise. In light of the rapidly increasing importance of pharmacogenomics in medical practice, Daly posits that improved pharmacogenetics teaching is vital.

ConclusionsOverall, despite its growing complexity, pharmacogenetics can still be helpful in predicting PK and/or PD in individual patients, particularly those receiving anticancer drugs, as emphasized by Gillis et al.21 Novel technical tools that accelerate discovery and diagnostics of genetic variants, as well as sophisticated bioinformatics models, may rapidly increase our understanding of the differential molecular background of diseases and patients’ therapeutic needs.22 These developments remain a scientific challenge but, increasingly, also an ethical and socioeconomic matter of public health, as indicated by the continuing debates over how to use and store genetic information and how to implement pharmacogenetics into national health-care systems and policies. Bridging basic research and clinical practice requires considerable effort and is much more complex than initially expected by many in this field. However, the lessons learned from individualized medicine in cancer23 and inflammatory diseases24 provide impetus to continue with the task of implementing pharmacogenetic knowledge into clinical medicine.

CONFLICT OF INTERESTR.T. has consulted for pharmaceutical companies, primarily in smoking cessation. She acknowledges support from the National Institutes of Health (PGRN grant DA020830) and Canadian Institutes of Health Research (MOP86471 and TMH 109787), as well as the Department of Psychiatry and the Centre for Addiction and Mental Health at the University of Toronto for her

Regulatory aspects of pharmacogeneticsGiven the progress toward a better understanding of the consequences of genomic variation, diseases may require new definitions and novel stratified treatment options. Hence, the current schemes of drug development may need to be reconsidered and reshaped by regulatory authorities, as outlined by Pacanowski et al., who review the regulatory processes and present considerations for the future.19 So far the US Food and Drug Administration (FDA) has labeled approximately 100 drugs as being associated with genetic variation. The authors explain that such labeling was introduced to give dosing instructions or warnings, particularly for drugs to be taken by patients at higher risk for toxicity or therapeutic failure because of metabolism by polymorphic enzymes, analogous to what is done to avoid drug–drug interactions. Moreover, the FDA uses labeling to inform prescribers about serious safety issues, including drugs that have been in use for decades. The increasing complexity of molecular biomarkers associated with drug efficacy and safety, as well as the ways in which new and established drugs should be approved and evaluated, is an increasing challenge for regulatory authorities worldwide. In particular, there is a need for interdisciplinary expertise. An additional issue involves appropriate regulation of genotyping, as indicated by the recent publicity surrounding the interactions between the FDA and the genomics company 23andMe.

Teaching pharmacogeneticsIn her Opinion piece,20 Daly stresses the necessity of expanding pharmacogenetics education, noting that in surveys on pharmacogenetics education in the United States and the United Kingdom, three-quarters of respondents said that

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genetic determinants of warfarin dose. PLoS Genet. 5, e1000433 (2009).

13. Perera, M.A. et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet 382, 790–796 (2013).

14. Jamshidi, Y. et al. Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia. J Am. Coll. Cardiol. 60, 841–850 (2012).

15. van Gelder, T., van Schaik, R.H. & Hesselink, D.A. Practicability of pharmacogenetics in transplantation medicine. Clin. Pharmacol. Ther. 95, 262–264 (2014).

16. Barry, A. & Levine, M. A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. Ther. Drug Monit. 32, 708–714 (2010).

17. Press, R.R., de Fijter, J.W. & Guchelaar, H.J. Individualizing calcineurin inhibitor therapy in renal transplantation—current limitations and perspectives. Curr. Pharm. Des. 16, 176–186 (2010).

18. Crettol, S., de Leon, J., Hiemke, C. & Eap, C.B. Pharmacogenomics in psychiatry: from therapeutic drug monitoring. Clin. Pharmacol. Ther. 95, 254–257 (2014).

19. Pacanowski, M.A., Leptak, C. & Zineh, I. Next-generation medicines: past regulatory experience and considerations for the future. Clin. Pharmacol. Ther. 95, 247–249 (2014).

20. Daly, A.K. Is there a need to teach pharmacogenetics? Clin. Pharmacol. Ther. 95, 245–247 (2014).

21. Gillis, N.K., Patel, J.N. & Innocenti, F. Clinical implementation of germ line cancer pharmacogenetic variants during the next-generation sequencing era. Clin. Pharmacol. Ther. 95, 269–280 (2014).

22. Ulahannan, D., Kovac, M.B., Mulholland, P.J., Cazier, J.B. & Tomlinson, I. Technical and implementation issues in using next-generation sequencing of cancers in clinical practice. Br. J. Cancer 109, 827–835 (2013).

23. Rosell, R., Bivona, T.G. & Karachaliou, N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet 382, 720–731 (2013).

24. Bendtzen, K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. Discov. Med. 15, 201–211 (2013).

endowed chair in Addictions. I.C. has consulted for pharmaceutical companies, primarily in pain treatment. He acknowledges support from the German Federal Ministry of Education and Research (01EY1103) and EU InterReg IVa.

© 2014 ASCPT

1. Relling, M.V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin. Pharmacol. Ther. 93, 324–325 (2013).

2. Roden, D.M. & Tyndale, R.F. Genomic medicine, precision medicine, personalized medicine: what’s in a name? Clin. Pharmacol. Ther. 94, 169–172 (2013).

3. Kalow, W. Pharmacogenetics in biological perspective. Pharmacol. Rev. 49, 369–379 (1997).

4. Wang, D., Guo, Y., Wrighton, S.A., Cooke, G.E. & Sadee, W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 11, 274–286 (2011).

5. Zanger, U.M. et al. Genetics, epigenetics, and regulation of drug-metabolizing cytochrome P450 enzymes. Clin. Pharmacol. Ther. 95, 258–261 (2014).

6. McDermott, U., Downing, J.R. & Stratton, M.R. Genomics and the continuum of cancer care. N. Engl. J. Med. 364, 340–350 (2011).

7. Turner, R.M. & Pirmohamed, M. Cardiovascular pharmacogenomics: expectations and practical benefits. Clin. Pharmacol. Ther. 95, 281–293 (2014).

8. Perera, M.A., Cavallari, L.H. & Johnson, J.A. Warfarin pharmacogenetics: an illustration of why studies in minority populations are important. Clin. Pharmacol. Ther. 95, 242–244 (2014).

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

10. Kimmel, S.E. et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N. Engl. J. Med. 369, 2283–2293 (2013).

11. Schwarz, U.I. et al. Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med. 358, 999–1008 (2008).

12. Takeuchi, F. et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal