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Moving towards individualized medicine with pharmacogenomics

Abstract

Individuals respond differently to drugs and sometimes the effects are unpredictable. Differences in DNA that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals. Many of the genes examined in early studies were linked to highly penetrant, single-gene traits, but future advances hinge on the more difficult challenge of elucidating multi-gene determinants of drug response. This intersection of genomics and medicine has the potential to yield a new set of molecular diagnostic tools that can be used to individualize and optimize drug therapy.

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Figure 1: Identifying genes influencing polygenic drug responses.
Figure 2: Evidence linking candidate gene polymorphisms to phenotypes can come from several sources. The matrix in the centre shows candidate genes that may be related to the phenotypes of interest.

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References

  1. Evans, W. E. & Relling, M. V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).

    Article  CAS  Google Scholar 

  2. Vesell, E. S. Pharmacogenetic perspectives gained from twin and family studies. Pharmacol. Ther. 41, 535–552 (1989).

    Article  CAS  Google Scholar 

  3. Guengerich, F. P. et al. Twenty years of biochemistry of human P450s: purification, expression, mechanism, and relevance to drugs. Drug Metab. Dispos. 26, 1175–1178 (1998).

    CAS  PubMed  Google Scholar 

  4. Meyer, U. A. & Zanger, U. M. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu. Rev. Pharmacol. Toxicol. 37, 269–296 (1997).

    Article  CAS  Google Scholar 

  5. Gonzalez, F. J. et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331, 442–446 (1988).

    Article  ADS  CAS  Google Scholar 

  6. Evans, W. E. & Johnson, J. A. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet. 2, 9–39 (2001).

    Article  CAS  Google Scholar 

  7. Weinshilboum, R. Inheritance and drug response. N. Engl. J. Med. 348, 529–537 (2003).

    Article  Google Scholar 

  8. Evans, W. E. & McLeod, H. L. Pharmacogenomics — drug disposition, drug targets, and side effects. N. Engl. J. Med. 348, 538–549 (2003).

    Article  CAS  Google Scholar 

  9. Evans, W. E. et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J. Clin. Oncol. 19, 2293–2301 (2001).

    Article  CAS  Google Scholar 

  10. Evans, W. E., Horner, M., Chu, Y. Q., Kalwinsky, D. & Roberts, W. M. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J. Pediatr. 119, 985–989 (1991).

    Article  CAS  Google Scholar 

  11. Marshall, E. Preventing toxicity with a gene test. Science 302, 588–590 (2003).

    Article  CAS  Google Scholar 

  12. Abbott, A. With your genes? Take one of these, three times a day. Nature 425, 760–762 (2003).

    Article  ADS  CAS  Google Scholar 

  13. Phillips, K. A., Veenstra, D. L., Oren, E., Lee, J. K. & Sadee, W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. J. Am. Med. Assoc. 286, 2270–2279 (2001).

    Article  CAS  Google Scholar 

  14. Eichelbaum, M., Spannbrucker, N. & Dengler, H. J. N-oxidation of sparteine in man and its interindividual differences. Naunyn Schmiedebergs Arch. Pharmacol. 287, R94 (1975).

    PubMed  Google Scholar 

  15. Mahgoub, A., Idle, J. R., Dring, L. G., Lancaster, R. & Smith, R. L. Polymorphic hydroxylation of Debrisoquine in man. Lancet 2, 584–586 (1977).

  16. Ingelman-Sundberg, M., Oscarson, M. & McLellan, R. A. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol. Sci. 20, 342–349 (1999).

    Article  CAS  Google Scholar 

  17. Cheok, M. H. et al. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nature Genet. 34, 85–90 (2003).

    Article  CAS  Google Scholar 

  18. Buetow, K. H. et al. High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc. Natl Acad. Sci. USA 98, 581–584 (2001).

    Article  ADS  CAS  Google Scholar 

  19. Liotta, L. A., Kohn, E. C. & Petricoin, E. F. Clinical proteomics: personalized molecular medicine. J. Am. Med. Assoc. 286, 2211–2214 (2001).

    Article  CAS  Google Scholar 

  20. Golub, T. R. Mining the genome for combination therapies. Nature Med. 9, 510–511 (2003).

    Article  CAS  Google Scholar 

  21. Stegmaier, K. et al. Gene expression-based high-throughput screening (GE-HTS) and application to leukemia differentiation. Nature Genet. 36, 257–263 (2004).

    Article  CAS  Google Scholar 

  22. Evans, W. E. & Guy, R. K. Gene expression as a drug discovery tool. Nature Genet. 36, 214–215 (2004).

    Article  CAS  Google Scholar 

  23. Mallal, S. et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359, 727–732 (2002).

  24. Kuehl, P. et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genet. 27, 383–391 (2001).

    Article  CAS  Google Scholar 

  25. Holden, C. Race and medicine. Science 302, 594–596 (2003).

    Article  CAS  Google Scholar 

  26. Rosenberg, N. A. et al. Genetic structure of human populations. Science 298, 2381–2385 (2002).

    Article  ADS  CAS  Google Scholar 

  27. Burchard, E. G. et al. The importance of race and ethnic background in biomedical research and clinical practice. N. Engl. J Med. 348, 1170–1175 (2003).

    Article  Google Scholar 

  28. Eccles, D. M. Genetic testing for BRCA1 mutation in the UK. Lancet 361, 178–179 (2003).

    Article  Google Scholar 

  29. Altman, R. B. et al. Indexing pharmacogenetic knowledge on the World Wide Web. Pharmacogenetics 13, 3–5 (2003).

    Article  Google Scholar 

  30. Goldstein, D. B., Tate, S. K. & Sisodiya, S. M. Pharmacogenetics goes genomic. Nature Rev. Genet. 4, 937–947 (2003).

    Article  CAS  Google Scholar 

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Competing interests

W.E.E. is an inventor on a US patent for the molecular diagnosis of TPMT non-functional alleles. He receives no direct remuneration for royalties, and freely provides protocols and reagents for research purposes.

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Evans, W., Relling, M. Moving towards individualized medicine with pharmacogenomics. Nature 429, 464–468 (2004). https://doi.org/10.1038/nature02626

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