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Pharmacogenetics and the practice of medicine

Abstract

“If it were not for the great variability among individuals medicine might as well be a science and not an art.” The thoughts of Sir William Osler in 1892 reflect the view of medicine over the past 100 years. The role of physicians in making the necessary judgements about the medicines that they prescribe is often referred to as an art, reflecting the lack of objective data available to make decisions that are tailored to individual patients. Just over a hundred years later we are on the verge of being able to identify inherited differences between individuals which can predict each patient's response to a medicine. This ability will have far-reaching benefits in the discovery, development and delivery of medicines. Sir William Osler, if he were alive today, would be re-considering his view of medicine as an art not a science.

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Figure 1: Genetics and genomics to identify drug targets.
Figure 2: Significance of SNP allele frequency differences in an affected Alzheimer's disease population and age-matched controls.
Figure 3: Linkage disequilibrium data for 12 adjacent SNPs that are located and ordered within the 120-kilobase region encoding a migraine susceptibility gene (in this instance, a D′ value above 0.30 is indicative of highly significant linkage disequilibrium).
Figure 4: The development of a pharmacogenetic medicine response profile.
Figure 5: ‘Genetic testing’ needs to be defined carefully.

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References

  1. Curran, M. E. Potassium ion channels and human disease: phenotypes to drug targets? Curr. Opin. Biotechnol. 9, 565–572 (1998).

    Article  CAS  Google Scholar 

  2. Marton, M. J. et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Med. 4 , 1293–1301 (1998).

    Article  CAS  Google Scholar 

  3. Wiley, S. R. Genomics in the real world. Curr. Pharmaceut. Des. 4, 417–422 (1998).

    CAS  Google Scholar 

  4. Blackstock, W. P. & Weir, M. P. Proteomics: quantitative and physical mapping of cellular proteins. Trends Biotechnol. 17, 121–127 (1999).

    Article  CAS  Google Scholar 

  5. Kozian, D. H. & Kirschbaum, B. J. Comparative gene-expression analysis. Trends Biotechnol. 17, 73– 78 (1999).

    Article  CAS  Google Scholar 

  6. Rockett, J. C., Esdaile, D. J. & Gibson, G. G. Differential gene expression in drug metabolism and toxicology: practicalities, problems and potential. Xenobiotica 29, 655–691 ( 1999).

    Article  CAS  Google Scholar 

  7. Roses, A. D. Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on APOE genotype and duration of disease. J. Neuropathol. Exp. Neurol. 53, 429–437 (1994).

    Article  CAS  Google Scholar 

  8. Saunders, A. M. Apolipoprotein E and Alzheimer's disease: an update on genetic and functional analyses. J. Neuropathol. Exp. Neurol. (in the press).

  9. Boschert, U., Merlo-Pich, E., Higgins, G., Roses, A. D. & Catsicas, S. Apolipoprotein E expression by neurons surviving excitotoxic stress. Neurobiol. Dis. 6, 508–514 (1999).

    Article  CAS  Google Scholar 

  10. Xu, P. T. et al. Human apolipoprotein E2, E3 and E4 isoform-specific transgenic mice: human-like pattern of neuronal immunoreactivity in central nervous system not observed in wild type mice. Neurobiol. Dis. 3, 229–245 (1996).

    Article  CAS  Google Scholar 

  11. Xu, P. T. et al. Regionally specific neuronal expression of human APOE gene in transgenic mice. Neurosci. Lett. 246, 65 –68 (1998).

    Article  CAS  Google Scholar 

  12. Xu, P. T. et al. Specific regional transcription of apolipoprotein E in human brain neurons. Am. J. Pathol. 154, 601– 611 (1999).

    Article  CAS  Google Scholar 

  13. Huang, J. T. et al. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378–382 (1999).

    Article  ADS  CAS  Google Scholar 

  14. Kliewer, S. A. Lehmann, J. M. & Wilson, T. M. Orphan nuclear receptors: shifting endocrinology into reverse. Science 284, 757– 760 (1999).

    Article  ADS  CAS  Google Scholar 

  15. Barroso, I. et al. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402, 880–883 ( 1999).

    Article  ADS  CAS  Google Scholar 

  16. Roses, A. D. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu. Rev. Med. 47, 387–400 (1996).

    Article  CAS  Google Scholar 

  17. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    Article  ADS  CAS  Google Scholar 

  18. Levy-Lehad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973– 977 (1995).

    Article  ADS  Google Scholar 

  19. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995).

    Article  ADS  CAS  Google Scholar 

  20. Van Nostrand, W. E., Wagner, S. L., Haan, J., Bakker, E. & Roos, R. A. Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type share a decrease in cerebrospinal fluid levels of amyloid beta-protein precursor. Ann. Neurol. 32, 215–218 (1992).

    Article  Google Scholar 

  21. Aitman, T. J. & Todd, J. A. Molecular genetics of diabetes mellitus . Baillieres Clin. Endocrinol. Metabol. 9, 631–656 (1995).

    Article  CAS  Google Scholar 

  22. Sandford, A., Weir, T. & Pare, P. The genetics of asthma. . Am. J. Respir. Crit. Care Med. 153, 1749–1765 (1996).

    Article  CAS  Google Scholar 

  23. Schork, N. J. Genetics of complex disease: approaches, problems, and solutions. Am. J. Respir. Crit. Care Med. 156, S103– S109 (1997).

    Article  CAS  Google Scholar 

  24. Concannon, P. et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 19, 292–296 (1998).

    Article  CAS  Google Scholar 

  25. Howard, T. D. et al. Genetics of allergy and bronchial hyperresponsiveness. Clin. Exp. Allergy 29(Suppl.), 86– 89 (1999).

    PubMed  Google Scholar 

  26. Talley, N. J. Irritable bowel syndrome: disease definition and symptom description. Eur. J. Surg. 583(Suppl.), 24– 28 (1998).

    Article  Google Scholar 

  27. Paterson, W. G. et al. Recommendations for the management of irritable bowel syndrome in family practice. IBS Consensus Conference Participants. Can. Med. Assoc. J. 161, 154–160 (1999).

    CAS  Google Scholar 

  28. Hamm, L. R. et al. Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome criteria. Am. J. Gastroenterol. 94, 1279–1282 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. 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 

  31. Cohen, L. J. & DeVane, C. L. Clinical Implications of antidepressant pharmacokinetics and pharmacogenetics. Ann. Pharmacotherapy 3, 1471–1480 (1996).

    Article  Google Scholar 

  32. Rudorfer, M. V., Lane, E. A., Chang, W. H., Zhang, M. & Potter, W. Z. Desipramine pharmacokinetics in Chinese and Caucasian volunteers. Br. J. Clin. Pharmacol. 17, 433–440 (1984).

    Article  CAS  Google Scholar 

  33. Mueller, R. F. & Young, I. D. in Emery's Elements of Medical Genetics (ed. Kalow, W.) 169–175 (Churchill Livingstone, Edinburgh, 1997).

    Google Scholar 

  34. Zhao, L. P., Aragaki, C., Hsu, L. & Quiaoit, F. Mapping of complex traits by single-nucleotide polymorphisms. Am. J. Hum. Genet. 63, 225–240 (1998).

    Article  CAS  Google Scholar 

  35. Brookes, A. J. The essence of SNPs. Gene 234, 177– 186 (1999).

    Article  CAS  Google Scholar 

  36. Hacia, J. G. et al. Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays. Nature Genet. 22, 164–167 ( 1999).

    Article  CAS  Google Scholar 

  37. Marez, D. et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 7, 193– 202 (1997).

    Article  CAS  Google Scholar 

  38. McKusick, V. A. Foreword to Mendelian Inheritance in Man 10th edn, vol. 1 , xv–xxxvii (The Johns Hopkins University Press, Baltimore, 1992).

    Google Scholar 

  39. Lai, E., Riley, J., Purvis, I. & Roses, A. A 4-Mb high-density single nucleotide polymorphism-based map around human APOE. Genomics 54, 31–38 ( 1998).

    Article  CAS  Google Scholar 

  40. Martin, E. R. et al. Analysis of association at single nucleotide polymorphisms in the APOE region. Genomics 63, 7– 12 (2000).

    Article  CAS  Google Scholar 

  41. Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139– 144 (1999).

    Article  CAS  Google Scholar 

  42. Collins, A., Lonjou, C. & Morton, N. E. Genetic epidemiology of single-nucleotide polymorphisms . Proc. Natl Acad. Sci. USA. 96, 15173– 15177 (1999).

    Article  ADS  CAS  Google Scholar 

  43. Ott, J. Predicting the range of linkage disequilibrium. Proc. Natl Acad. Sci. USA. 97, 2–3 (2000 ).

    Article  ADS  CAS  Google Scholar 

  44. Chen, J. et al. Microsphere-based assay for single-nucleotide polymorphism analysis using single base chain extension. Genome Res. 10, 549–557 (2000).

    Article  CAS  Google Scholar 

  45. Roses, A. D., Manasco, P. & Freeman, A. J. Pharmacogenetics and genetics to discover new medicines . J. Comm. Biotech. (in the press).

  46. Roses, A. D. Pharmacogenetics and the future of drug development and delivery. Lancet 355, 1358–1361 ( 2000).

    Article  CAS  Google Scholar 

  47. Alon, U. et al. Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays. Proc. Natl Acad. Sci. USA 96, 6745– 6750 (1999).

    Article  ADS  CAS  Google Scholar 

  48. Bonnie, A., Fijal, M. S., Hall, J. M. & Witte, J. S. Clinical trials in the genomic era. Effects of protective genotypes on sample size and duration of trial 2000. Controlled Clin. Trials 21, 7–20 (2000).

    Article  Google Scholar 

  49. Lazarou, J., Pomeranz, B. H. & Corey, P. N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. J. Am. Med. Assoc. 279, 1200–1205 ( 1998).

    Article  CAS  Google Scholar 

  50. Wood, A. J., Stein, C. M. & Woosley, R. Making medicines safer—the need for an independent drug safety board. N. Engl. J. Med. 339, 1851–1854 (1998).

    Article  CAS  Google Scholar 

  51. White, J. Targets and systems of health care cost control. J. Health Politics Policy Law 24, 653–696 ( 1999).

    Article  CAS  Google Scholar 

  52. Mather, D. B., Sullivan, S. D., Augustein, D., Fullerton, P. & Atherton, D. Incorporating clinical outcomes and economic consequences into drug formulary decision: a practical approach . Am. J. Man. Care 5, 277– 285 (1999).

    CAS  Google Scholar 

  53. McConnell, L. M. B. et al. Genetic testing and Alzheimer disease: recommendations of the Stanford Program in Genomics, Ethics, and Society. Genetic Testing 3, 3–12 ( 1999).

    Article  CAS  Google Scholar 

  54. Koenig, B. A., Greely, H. T., McConnell, L. M., Silveberg, H. L. & Raffin, T. A. Genetic testing for BRCA1 and BRCA2: recommendations of the Stanford Program in Genomics, Ethics, and Society. Breast Cancer Working Group. J. Womens Health 7, 531–545 ( 1998).

    Article  CAS  Google Scholar 

  55. Taningher, M., Malacarne, D., Izzotti, A., Ugolini, D. & Parodi, S. Drug metabolism polymorphisms as modulators of cancer susceptibility. Mutation Res. 436, 227–261 (1999).

    Article  CAS  Google Scholar 

  56. Saunders, A. M. et al. Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease. Lancet 348, 90–93 (1996).

    Article  CAS  Google Scholar 

  57. Mayeux, R., et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's disease Centers Consortium on Apolipoprotein E and Alzheimer's disease. N. Engl. J. Med. 338, 506–511 (1998). [Published erratum appears in N. Engl. J. Med. 338, 1325 (1998).]

    Article  CAS  Google Scholar 

  58. Roses, A. D. Genetic testing for Alzheimer disease. Practical and ethical issues. Arch. Neurol. 54, 1226–1229 (1997).

    Article  CAS  Google Scholar 

  59. Roses, A. D. Apolipoprotein E is a relevant susceptibility gene that affects the rate of expression of Alzheimer's disease. Neurobiol. Aging 15(Suppl 2), S165–S167 ( 1994).

    Article  Google Scholar 

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Acknowledgements

I acknowledge my colleagues at Glaxo Wellcome in the development of the strategies outlined in this review; in particular, the vision and support of J. Niedel and the commitment of the Glaxo Wellcome R&D Executive Committee — A. Baxter, T. Eaves, A. Hennah and J. Palmer — in using their wealth of experience to help make this vision become a reality. I also thank the Genetics Directorate at Glaxo Wellcome for their expertise and continued hard work. Some of the recent pre-publication work carried out by Glaxo Wellcome scientists is reviewed in this paper. I especially thank A. Freeman, A. Saunders and A. Kidgell for expert editorial assistance.

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Roses, A. Pharmacogenetics and the practice of medicine. Nature 405, 857–865 (2000). https://doi.org/10.1038/35015728

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