Opinion | Published:

Creating and evaluating genetic tests predictive of drug response

Nature Reviews Drug Discovery volume 7, pages 568574 (2008) | Download Citation


A key goal of pharmacogenetics — the use of genetic variation to elucidate inter-individual variation in drug treatment response — is to aid the development of predictive genetic tests that could maximize drug efficacy and minimize drug toxicity. The completion of the Human Genome Project and the associated HapMap Project, together with advances in technologies for investigating genetic variation, have greatly advanced the potential to develop such tests; however, many challenges remain. With the aim of helping to address some of these challenges, this article discusses the steps that are involved in the development of predictive tests for drug treatment response based on genetic variation, and factors that influence the development and performance of these tests.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  2. 2.

    et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

  3. 3.

    et al. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  4. 4.

    et al. Functional genomics of membrane transporters in human populations. Genome Res. 16, 223–230 (2006).

  5. 5.

    , , & Pharmacogenomics and clinical biomarkers in drug discovery and development. Am. J. Clin. Pathol. 124, S29–S41 (2005).

  6. 6.

    Challenges of drug discovery for personalized medicine. Curr. Opin. Mol. Ther. 8, 487–492 (2006).

  7. 7.

    et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608–614 (1997).

  8. 8.

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

  9. 9.

    et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype–genetype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14, 407–417 (2004).

  10. 10.

    , & Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J. Pharmacol. Exp. Ther. 278, 1165–1174 (1996).

  11. 11.

    et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287, 1690–1698 (2002).

  12. 12.

    et al. Sequence, haplotype and association analysis of ADRβ2 in multi-ethnic asthma case–control subjects. Am. J. Respir. Crit. Care Med. 174, 1101–1109 (2006).

  13. 13.

    et al. for the PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008).

  14. 14.

    et al. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab. Pharmacokinet. 20, 153–167 (2005).

  15. 15.

    , , & Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin. Pharmacokinet. 41, 913–958 (2002).

  16. 16.

    et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 352, 2285–2293 (2005).

  17. 17.

    , , & Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood 107, 843–844 (2006).

  18. 18.

    & Cancer pharmacogenetics. Br. J. Cancer 90, 8–11 (2004).

  19. 19.

    et al. Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples. Pharmacogenetics 13, 501–507 (2003).

  20. 20.

    , , & Concordance of pharmacogenetic markers in germline and colorectal tumor DNA. Pharmacogenomics 6, 873–877 (2005).

  21. 21.

    et al. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Nature Genet. 37, 878–882 (2005).

  22. 22.

    & Pharmacogenetics goes 3D. Nature Genet. 37, 794–795 (2005).

  23. 23.

    et al. ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J. Am. Soc. Nephrol. 16, 1501–1511 (2005).

  24. 24.

    et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl Cancer Inst. 97, 30–39 (2005).

  25. 25.

    et al. Relationship between diet and anticoagulant response to warfarin: a factor analysis. Eur. J. Nutr. 46, 147–154 (2007).

  26. 26.

    & The unfinished business of US drug regulation. Food Drug Law J. 61, 45–64 (2006).

  27. 27.

    et al. Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA–PWG–PhRMA–DruSafe Workshop. J. Clin. Pharmacol. 43, 342–358 (2003).

  28. 28.

    , & The impact of expression profiling on prognostic and predictive testing in breast cancer. J. Clin. Pathol. 59, 225–231 (2006).

  29. 29.

    et al. Concordance among gene-expression-based predictors for breast cancer. N. Engl. J. Med. 355, 560–569 (2006).

  30. 30.

    , , , & Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nature Genet. 37, 435–440 (2005).

  31. 31.

    ,. ,. & Clinical Epidemiology 2nd Edn (Little Brown, Boston, Massachusetts, 1991).

  32. 32.

    et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum. Mol. Genet. 13, 1353–1359 (2004).

Download references


We would like to thank Richard M. Weinshilboum, MD and the White Paper subcommittee of the PGRN network for valuable suggestions. Financial support is also acknowledged: U01 HL065899 (S.T.W.); U01 GM63340 (H.L.M.); UO1 GM061373 (D.A.F.); DA 20830 (N.L.B.); U01 GM074492 (J.A.J.); GM61393 (M.J.R. and M.E.D.); and GM61390 (K.M.G.).

Author information


  1. Scott T. Weiss is at the Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Ave, Boston, Massachusetts 02115, USA.

    • Scott T. Weiss
  2. Howard L. McLeod is at the University of North Carolina, Chapel Hill, Campus Box 7360, 3203 Kerr Hall, Chapel Hill, North Carolina 27599, USA.

    • Howard L. McLeod
  3. David A. Flockhart is at the Indiana University School of Medicine, Wishard Hospital, WD OPW 320, 1001 West 10th Street, Indianapolis, Indianapolis 46202, USA.

    • David A. Flockhart
  4. M. Eileen Dolan is at the Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, 5841 South Maryland Avenue, Box MC2115, University of Chicago, Chicago, Illinois 6063-71470, USA.

    • M. Eileen Dolan
  5. Neal L. Benowitz is at the Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, Box 1220, San Francisco, California 94143-1220, USA.

    • Neal L. Benowitz
  6. Julie A. Johnson is at the University of Florida College of Pharmacy, Department of Pharmacy Practice, P.O. Box 100486, Gainesville, Florida 32610-0486, USA.

    • Julie A. Johnson
  7. Mark J. Ratain is at the University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, Illinois 60637-1470, USA.

    • Mark J. Ratain
  8. Kathleen M. Giacomini is at the University of California, San Francisco, School of Pharmacy, Box 0446 513 Parnassus Avenue, San Francisco, California 94143-0446, USA.

    • Kathleen M. Giacomini


  1. Search for Scott T. Weiss in:

  2. Search for Howard L. McLeod in:

  3. Search for David A. Flockhart in:

  4. Search for M. Eileen Dolan in:

  5. Search for Neal L. Benowitz in:

  6. Search for Julie A. Johnson in:

  7. Search for Mark J. Ratain in:

  8. Search for Kathleen M. Giacomini in:

Corresponding author

Correspondence to Scott T. Weiss.


Environmental phenocopy

A clinical case of a complex trait due solely to environmental factors.


The interaction or interdependence of two or more genes.

Incomplete penetrance

Occurs when less than 100% of a population with an identical mutant genotype display the associated phenotype.

Linkage disequilibrium

The nonrandom association of alleles in the genome.

Mode of inheritance

Dominant mode of inheritance occurs when only one copy of the allele is necessary to produce the phenotype. Recessive mode of inheritance occurs when both copies of the allele are necessary to produce the phenotype.


A single mutation that has more than one biological effect or phenotype.

Receiver operating characteristic (ROC) curve

A curve that plots I-sensitivity on the y axis and specificity on the x axis. The area under this curve is a measure of test performance.

Severe adverse event

An event that occurs less than 1 in 10,000 administrations of the medication and is life threatening.

About this article

Publication history




Further reading