Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The genetic basis of variability in drug responses

Nature Reviews Drug Discovery volume 1, pages 37–44 (2002)Cite this article

Key Points

  • Variability in response to therapy is an expected feature of most drug treatments.

  • Pharmacokinetic variability arises because of variable delivery of a dose of a drug to target sites; that is, variability in the relationship between drug dose and plasma and tissue drug concentrations.

  • Pharmacodynamic variability arises because of variability in the relationship between drug concentration and effect.

  • In either case, variants in individual genes that mediate drug concentrations or their effects are increasingly being recognized as sources of variable drug action — 'pharmacogenetics'.

  • The sequencing of the human genome now raises the possibility of identifying many genetic variants, each contributing to overall variability in drug action: this is one definition of 'pharmacogenomics.'

  • We propose an algorithm for use in the pharmacogenomic profiling of adverse responses to drug action.

  • Although the vision of choosing 'personalized medicines' based on individual genetic profiles is an appealing one, substantial obstacles will need to be overcome if this is to become practical: these include logistic, analytical, biostatistical and ethical issues.

Abstract

It is almost axiomatic that patients vary widely in their beneficial responses to drug therapy, and serious and apparently unpredictable adverse drug reactions continue to be a major public health problem. Here, we discuss the concept that genetic variants might determine much of this variability in drug response, and propose an algorithm to enable further evaluation of the benefits and pitfalls of this enticing possibility.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Determinants of drug delivery to target sites.
Figure 2: Determinants of drug action at the target site.
Figure 3: An algorithm for evaluating the role of genetic factors in drug actions.

Similar content being viewed by others

References

  1. Kennedy, D. L., Johnson, J. M. & Nightingale, S. L. Monitoring of adverse drug events in hospitals. JAMA 266, 2878 (1991).

    Article  CAS  Google Scholar 

  2. Classen, D. C., Pestotnik, S. L., Evans, R. S., Lloyd, J. F. & Burke, J. P. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 277, 301–306 (1997).

    Article  CAS  Google Scholar 

  3. Dormann, H. et al. Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting. Drug Saf. 22, 161–168 (2000).

    Article  CAS  Google Scholar 

  4. Brewer, T. & Colditz, G. A. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 281, 824–829 (1999).

    Article  CAS  Google Scholar 

  5. 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. JAMA 286, 2270–2279 (2001).

    Article  CAS  Google Scholar 

  6. Motulsky, A. G., Harper, P. S., Bobrow, M. & Scriver, C. in Pharmacogenetics 1st edn (ed. Weber, W. W.) 1–20 (Oxford Univ. Press, New York, 1997).

    Google Scholar 

  7. Beutler, E., Dern, R. J. & Alving, A. S. The hemolytic effect of primaquine. VI. An in vitro test for sensitivity of erythrocytes to primaquine. J. Lab. Clin. Med. 45, 40–50 (1955).

    CAS  PubMed  Google Scholar 

  8. Price-Evans, D. A., Manley, F. A. & McKusick, V. A. Genetic control of isoniazid metabolism in man. Br. Med. J. 2, 485–491 (1960).

    Article  Google Scholar 

  9. Bönicke, R. & Lisboa, B. P. Uber die Erbbedingtheit der intraindividuellen Konstantz der Isoniazidausscheidung beim Menshen (Untersuchen an eineiggen und zweieiggen Zwilligen). Naturwissenschafften 44, 314 (1957).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Roses, A. D. Pharmacogenetics and the practice of medicine. Nature 405, 857–865 (2000).

    Article  CAS  Google Scholar 

  12. Meyer, U. A. Pharmacogenetics and adverse drug reactions. Lancet 356, 1667–1671 (2000).

    Article  CAS  Google Scholar 

  13. Woosley, R. L. et al. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N. Engl. J. Med. 298, 1157–1159 (1978).

    Article  CAS  Google Scholar 

  14. Grant, D. M., Blum, M. & Meyer, U. A. Polymorphisms of N-acetyltransferase genes. Xenobiotica 22, 1073–1081 (1992).

    Article  CAS  Google Scholar 

  15. Mahgoub, A., Idle, R. J., Dring, L. G., Lancaster, R. & Smith, R. L. Polymorphic hydroxylation of debrisoquine in man. Lancet 2, 584–586 (1977).Initial description of the clinical importance of the CYP2D6 polymorphism in drug disposition and drug action.

    Article  CAS  Google Scholar 

  16. Eichelbaum, M., Spannbrucker, N., Steincke, B. & Dengler, H. J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur. J. Clin. Pharmacol. 16, 183–187 (1979).

    Article  CAS  Google Scholar 

  17. Caraco, Y., Sheller, J. & Wood, A. J. Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects. J. Pharmacol. Exp. Ther. 290, 413–422 (1999).

    CAS  PubMed  Google Scholar 

  18. Brosen, K., Zeugin, T. & Meyer, U. A. Role of P450IID6, the target of the sparteine–debrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin. Pharmacol. Ther. 49, 609–617 (1991).

    Article  CAS  Google Scholar 

  19. Lee, J. T. et al. The role of genetically determined polymorphic drug metabolism in the β-blockade produced by propafenone. N. Engl. J. Med. 322, 1764–1768 (1990).

    Article  CAS  Google Scholar 

  20. Lennard, M. S. et al. Oxidation phenotype — a major determinant of metoprolol metabolism and response. N. Engl. J. Med. 307, 1558–1560 (1982).

    Article  CAS  Google Scholar 

  21. 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 

  22. Aithal, G. P., Day, C. P., Kesteven, P. J. & Daly, A. K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353, 717–719 (1999).

    Article  CAS  Google Scholar 

  23. Furuta, T. et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann. Intern. Med. 129, 1027–1030 (1998).

    Article  CAS  Google Scholar 

  24. Weinshilboum, R. Methyltransferase pharmacogenetics. Pharmacol. Ther. 43, 77–90 (1989).

    Article  CAS  Google Scholar 

  25. Ando, Y. et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 60, 6921–6926 (2000).

    CAS  Google Scholar 

  26. Glatt, H. et al. Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat. Res. 482, 27–40 (2001).

    Article  CAS  Google Scholar 

  27. Forbat, A., Lond, M. B., Lehmann, H. & Silk, E. Prolonged apnea following injection of succinylcholine. Lancet 2, 1067–1068 (1953).

    Google Scholar 

  28. Whittaker, M. Genetic aspects of succinylcholine sensitivity. Anesthesiology 32, 143–150 (1970).

    Article  CAS  Google Scholar 

  29. Vandel, S. et al. Tricyclic antidepressant plasma levels after fluoxetine addition. Neuropsychobiology 25, 202–207 (1992).

    Article  CAS  Google Scholar 

  30. Woosley, R. L., Chen, Y., Freiman, J. P. & Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. J. Am. Med. Assoc. 269, 1532–1536 (1993).Identification of the pharmacokinetic and ion-channel blocking mechanisms that underlie the potentially fatal cardiotoxicity that is associated with the widely used antihistamine terfenadine.

    Article  CAS  Google Scholar 

  31. Fromm, M. F., Kim, R. B., Stein, C. M., Wilkinson, G. R. & Roden, D. M. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 99, 552–557 (1999).

    Article  CAS  Google Scholar 

  32. Kim, R. B. et al. P-glycoprotein transporter limits oral absorption and brain entry of HIV protease inhibitors. J. Clin. Invest. 101, 289–294 (1998).HIV-protease inhibitors access the CNS in mice with disrupted P-glycoprotein, a potential explanation for the CNS as a viral 'sanctuary site' in protease-inhibitor therapy.

    Article  CAS  Google Scholar 

  33. Hoffmeyer, S. et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA 97, 3473–3478 (2000).

    Article  CAS  Google Scholar 

  34. Kim, R. B. et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 70, 189–199 (2001).

    Article  CAS  Google Scholar 

  35. Schinkel, A. H. et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77, 491–502 (1994).

    Article  CAS  Google Scholar 

  36. 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 

  37. Lehmann, J. M. et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016–1023 (1998).Regulation of expression of functionally normal genes as a mechanism that underlies drug action.

    Article  CAS  Google Scholar 

  38. Smirlis, D., Muangmoonchai, R., Edwards, M., Phillips, I. R. & Shephard, E. A. Orphan receptor promiscuity in the induction of cytochromes p450 by xenobiotics. J. Biol. Chem. 276, 12822–12826 (2001).

    Article  CAS  Google Scholar 

  39. Synold, T. W., Dussault, I. & Forman, B. M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med. 7, 584–590 (2001).

    Article  CAS  Google Scholar 

  40. Xie, W. et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev. 14, 3014–3023 (2000).

    Article  CAS  Google Scholar 

  41. Xie, W. et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435–439 (2000).

    Article  CAS  Google Scholar 

  42. Poirier, J. et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc. Natl Acad. Sci. USA 92, 12260–12264 (1995).

    Article  CAS  Google Scholar 

  43. Sesti, F. et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl Acad. Sci. USA 97, 10613–10618 (2000).

    Article  CAS  Google Scholar 

  44. Drazen, J. M. et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 22, 168–170 (1999).Shows that a promoter polymorphism regulates the expression of a drug target, and therefore drug effect.

    Article  CAS  Google Scholar 

  45. Donger, C. et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 96, 2778–2781 (1997).

    Article  CAS  Google Scholar 

  46. Napolitano, C. et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J. Cardiovasc. Electrophysiol. 11, 691–696 (2000).

    Article  CAS  Google Scholar 

  47. Yang, P. et al. Frequency of ion channel mutations and polymorphisms in a large population of patients with drug-associated Long QT Syndrome. Pacing Clin. Electrophys. 24, 579 (2001).

    Google Scholar 

  48. Wei, J. et al. KCNE1 polymorphism confers risk of drug-induced long QT syndrome by altering kinetic properties of IKs potassium channels. Circulation 100, 1–495 (1999).

    Google Scholar 

  49. Rigat, B. et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86, 1343–1346 (1990).

    Article  CAS  Google Scholar 

  50. Ueda, S., Meredith, P. A., Morton, J. J., Connell, J. M. & Elliott, H. L. ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans. Circulation 98, 2148–2153 (1998).

    Article  CAS  Google Scholar 

  51. McNamara, D. M. et al. Pharmacogenetic interactions between β-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 103, 1644–1648 (2001).Variability in response to β-blocker therapy in heart failure due to a polymorphism in the ACE gene, the activity of which determines the biological context in which β-blockers act.

    Article  CAS  Google Scholar 

  52. Vesell, E. S. & Page, J. G. Genetic control of drug levels in man: antipyrine. Science 161, 72–73 (1968).

    Article  CAS  Google Scholar 

  53. Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).

    Article  CAS  Google Scholar 

  54. Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).

    Article  CAS  Google Scholar 

  55. Stephens, J. C. et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493 (2001).

    Article  CAS  Google Scholar 

  56. Judson, R. & Stephens, J. C. Notes from the SNP vs haplotype front. Pharmacogenomics 2, 7–10 (2001).

    Article  CAS  Google Scholar 

  57. Otterness, D. M., Szumlanski, C. L., Wood, T. C. & Weinshilboum, R. M. Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. J. Clin. Invest. 101, 1036–1044 (1998).

    Article  CAS  Google Scholar 

  58. McLeod, H. L., Krynetski, E. Y., Relling, M. V. & Evans, W. E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14, 567–572 (2000).The activity of thiopurine methyltransferase determines both the efficacy and the severe toxicity of drug therapy for the treatment of acute lymphoblastic leukaemia and, in some centres, genotyping to guide dosage is now routine; probably the first example of pre-prescription genotyping in clinical practice.

    Article  CAS  Google Scholar 

  59. Rothstein, M. A. & Epps, P. G. Ethical and legal implications of pharmacogenomics. Nature Rev. Genet. 2, 228–231 (2001).

    Article  CAS  Google Scholar 

  60. Robertson, J. A. Consent and privacy in pharmacogenetic testing. Nature Genet. 28, 207–209 (2001).Discusses the substantial ethical issues involved in genetic and, especially, in pharmacogenetic studies.

    Article  CAS  Google Scholar 

  61. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med. 325, 293–302 (1991).

  62. Pfeffer, M. A. et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N. Engl. J. Med. 327, 669–677 (1992).

    Article  CAS  Google Scholar 

  63. Brown, N. J., Ray, W. A., Snowden, M. & Griffin, M. R. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin. Pharmacol. Ther. 60, 8–13 (1996).

    Article  CAS  Google Scholar 

  64. Brown, N. J., Snowden, M. & Griffin, M. R. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. J. Am. Med. Assoc. 278, 232–233 (1997).

    Article  CAS  Google Scholar 

  65. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).

  66. Shepherd, J. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333, 1301–1307 (1995).

    Article  CAS  Google Scholar 

  67. Ucar, M., Mjorndal, T. & Dahlqvist, R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf. 22, 441–457 (2000).

    Article  CAS  Google Scholar 

  68. Kleyn, P. W. & Vesell, E. S. Genetic variation as a guide to drug development. Science 281, 1820–1821 (1998).

    Article  CAS  Google Scholar 

  69. Mamiya, K. et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 39, 1317–1323 (1998).

    Article  CAS  Google Scholar 

  70. Sullivan-Klose, T. H. et al. The role of the CYP2C9 Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6, 341–349 (1996).

    Article  CAS  Google Scholar 

  71. Wedlund, P. J., Aslanian, W. S., McAllister, C. B., Wilkinson, G. R. & Branch, R. A. Mephenytoin hydroxylation deficiency in caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin. Pharmacol. Ther. 36, 773–780 (1984).

    Article  CAS  Google Scholar 

  72. Dahl, M.-L., Johansson, I., Bertilsson, L., Ingelman-Sundberg, M. & Sjoeqvist, F. Ultrarapid hydroxylation of debrisoquine in a Swedish population: analysis of the molecular genetic basis. J. Pharmacol. Exp. Ther. 274, 516–520 (1995).

    CAS  PubMed  Google Scholar 

  73. Edeki, T. I., He, H. & Wood, A. J. Pharmacogenetic explanation for excessive β-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction. J. Am. Med. Assoc. 274, 1611–1613 (1995).

    Article  CAS  Google Scholar 

  74. Zhou, H. H. & Wood, A. J. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin. Pharmacol. Ther. 57, 518–524 (1995).

    Article  CAS  Google Scholar 

  75. Idle, J. R., Mahgoub, A., Lancaster, R. & Smith, R. L. Hypotensive response to debrisoquine and hydroxylation phenotype. Life Sci. 22, 979–984 (1978).

    Article  CAS  Google Scholar 

  76. Ellard, G. A., Mitchison, D. A., Girling, D. J., Nunn, A. J. & Fox, W. The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug. Am. Rev. Respir. Dis. 118, 628–629 (1978).

    CAS  PubMed  Google Scholar 

  77. Stolk, J. N. et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 41, 1858–1866 (1998).

    Article  CAS  Google Scholar 

  78. Israel, E. et al. The effect of polymorphisms of the β(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am. J. Respir. Crit. Care Med. 162, 75–80 (2000).

    Article  CAS  Google Scholar 

  79. Lutucuta, S., Ballantyne, C. M., Elghannam, H., Gotto, A. M. Jr, & Marian, A. J. Novel polymorphisms in promoter region of ATP binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy. Circ. Res. 88, 969–973 (2001).

    Article  CAS  Google Scholar 

  80. Kuivenhoven, J. A. et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N. Engl. J. Med. 338, 86–93 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Work in D.M.R.'s laboratory is supported in part by grants from the United States Public Health Service. D.M.R. holds the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi Corporation.

Author information

Authors and Affiliations

  1. Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, 532 Robinson Research Building, Nashville, 37232, Tennessee, USA

    Dan M. Roden & Alfred L. George Jr

Authors
  1. Dan M. Roden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alfred L. George Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dan M. Roden.

Related links

Related links

DATABASES

FlyBase

ether a go-go

LocusLink

ACE

APOE

choline acetyltransferase

CYP2D6

CYP2C9

CYP2C19

CYP3A4

glucose-6-phosphate dehydrogenase

HERG

HMG CoA reductase

KCNE2

5-lipoxygenase

thiopurine methyltransferase

Medscape DrugInfo

isoniazid

erythromycin

ketoconazole

tacrine

6-mercaptopurine

zileuton

OMIM

Alzheimer's disease

FURTHER INFORMATION

Human Cytochrome P450 Allele Nomenclature Committee

National Institutes of Health

Pharmacogenetics Research Network and Knowledge Base

Glossary

ALKAPTONURIA

One of the earliest recognized “inborn errors of metabolism”, arising from the inheritance of two abnormal copies of the gene (recessive inheritance) that encodes homogentisic acid oxidase. The symptoms include arthritis and pigmented urine.

PHENOTYPE

The clinical presentation or characteristics.

ALLELES

Different versions of the same gene, one inherited from the mother and one from the father.

NUCLEAR ORPHAN RECEPTOR

An analogue of a known nuclear receptor (often for a hormone) with no putative ligand yet identified.

GENOTYPE

The genetic sequences that define the specific alleles that are present in an individual.

QT INTERVAL

The QT interval represents the time for electrical activation and inactivation of the ventricles — the lower chambers of the heart. Prolongation of the QT interval can result in the potentially lethal arrhythmia known as Torsades de Pointes.

HOMOZYGOUS

Two identical alleles at a gene or locus.

MUTATION

A DNA variant that occurs rarely, and is often associated with disease.

POLYMORPHISMS

Variants that are common (by definition greater than 1% of a given population), which can, in some cases, change an encoded amino acid, and have also been linked with altered gene function.

POSITIONAL CLONING

An experimental technique to identify genes that contribute to a phenotype by first identifying the chromosomal locus (position). Positional cloning makes no assumptions as to underlying physiology, and so can identify genes with relationships to a specified phenotype that had not previously been suspected.

HAPLOTYPE

The arrangement of individual alleles on a chromosome.

NON-SYNONYMOUS CODING-REGION POLYMORPHISM

A DNA polymorphism in the coding region of a gene that results in a change in the encoded amino acid.

SYNONYMOUS CODING-REGION POLYMORPHISM

A DNA polymorphism in the coding region of a gene that does not result in a change in the encoded amino acid.

LINKAGE DISEQUILIBRIUM

The association between a pair of allelic variants that occurs more often than by chance.

BONE MARROW APLASIA

Failure of the bone marrow to produce blood elements; a rare, unpredictable, and potentially fatal effect of some drugs.

RHABDOMYOLYSIS

A syndrome of muscle damage that is sometimes provoked by drugs, which can cause fatal renal failure.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roden, D., George Jr, A. The genetic basis of variability in drug responses. Nat Rev Drug Discov 1, 37–44 (2002). https://doi.org/10.1038/nrd705

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd705

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing