Variable Drug Response: Genetic Evaluation


The field of pharmacogenomics attempts to evaluate the contribution of genetic variants to drug sensitivity and adverse effects. Over the past decade, the pharmacogenomics field has evolved from using candidate gene approaches to application of genome‚Äźwide approaches for the identification of genetic variants associated with drug responses. Understanding the underlying biology of these associations as well as their translation into clinical practice represents a major ongoing and future challenge.

Key Concepts:

  • A discussion on pharmacogenomics studies on drug response and adverse drug reactions.

  • History of pharmacogenomics

  • The ethnic component of pharmacogenomics

  • The impact of genetics on drug response

  • The impact of genetics on adverse drug reactions

  • Clinical implementation of pharmacogenomics

Keywords: pharmacogenomics; personalised medicine; pharmacoethnicity; drug response; adverse drug reactions

Figure 1.

The evolution of pharmacogenomics. The diagram depicts the different advantages and disadvantages for candidate gene approaches, candidate pathway genes approaches, genome‐wide association studies (GWAS) and next‐generation sequencing.

Reproduced with permission from Madian et al. . © Elsevier.


Aithal GP, Day CP, Kesteven PJ and Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353(9154): 717–719.

Carmody MS and Anderson JR (2007) BiDil (isosorbide dinitrate and hydralazine): a new fixed‐dose combination of two older medications for the treatment of heart failure in black patients. Cardiology in Review 15(1): 46–53.

Chung WH, Hung SI, Hong HS et al. (2004) Medical genetics: a marker for Stevens–Johnson syndrome. Nature 428(6982): 486.

Clayman CB, Arnold J, Hockwald RS et al. (1952) Toxicity of primaquine in Caucasians. Journal of the American Medical Association 149(17): 1563–1568.

Daly AK, Donaldson PT, Bhatnagar P et al. (2009) HLA‐B*5701 genotype is a major determinant of drug‐induced liver injury due to flucloxacillin. Nature Genetics 41(7): 816–819.

Davis JC, Furstenthal L, Desai AA et al. (2009) The microeconomics of personalized medicine: today's challenge and tomorrow's promise. Nature Reviews Drug Discovery 8(4): 279–286.

Eichelbaum M, Spannbrucker N, Steincke B and Dengler HJ (1979) Defective N‐oxidation of sparteine in man: a new pharmacogenetic defect. European Journal of Clinical Pharmacology 16(3): 183–187.

Epstein RS, Moyer TP, Aubert RE et al. (2010) Warfarin genotyping reduces hospitalization rates results from the MM‐WES (Medco‐Mayo Warfarin Effectiveness study). Journal of the American College of Cardiology 55(25): 2804–2812.

FDA (2013), ‘Guideline for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting’. Available at (accessed on 16 May 2013).

Fellay J, Thompson AJ, Ge D et al. (2010) ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464(7287): 405–408.

Ge D, Fellay J, Thompson AJ et al. (2009) Genetic variation in IL28B predicts hepatitis C treatment‐induced viral clearance. Nature 461(7262): 399–401.

Ghaddar F, Cascorbi I and Zgheib NK (2011) Clinical implementation of pharmacogenetics: a nonrepresentative explorative survey to participants of WorldPharma 2010. Pharmacogenomics 12: 1051–1059.

Harper AR and Topol EJ (2012) Pharmacogenomics in clinical practice and drug development. Nature Biotechnology 30(11): 1117–1124.

Hofmann WP and Zeuzem S (2011) A new standard of care for the treatment of chronic HCV infection. Nature Reviews Gastroenterology and Hepatology 8: 257–264.

Hughes HB, Biehl JP, Jones AP et al. (1954) Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. American Review of Tuberculosis 70(2): 266–273.

Hung SI, Chung WH, Jee SH et al. (2006) Genetic susceptibility to carbamazepine‐induced cutaneous adverse drug reactions. Pharmacogenetics and Genomics 16(4): 297–306.

Iyer L, Hall D, Das S et al. (1999) Phenotype‐genotype correlation of in vitro SN‐38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clinical Pharmacology and Therapeutics 65(5): 576–582.

Johnson JA (2013) Pharmacogenetics in clinical practice: how far have we come and where are we going?. Pharmacogenomics 14(7): 835–843.

Jolivet J, Cowan KH, Curt GA, Clendeninn NJ and Chabner BA (1983) The pharmacology and clinical use of methotrexate. New England Journal of Medicine 309(18): 1094–1104.

Krimsky S (2012) The short life of a race drug. Lancet 379(9811): 114–115.

Law M and Wald NJ (2006) Efficacy and safety of cholesterol‐lowering treatment. Lancet 367(9509): 469–470.

Lehmann H and Ryan E (1956) The familial incidence of low pseudocholinesterase level. Lancet 271(6934): 124.

Limdi NA, McGwin G, Goldstein JA et al. (2008) Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African‐American and European‐American patients on warfarin. Clinical Pharmacology and Therapeutics 83(2): 312–321.

Link E, Parish S, Armitage J et al. (2008) SLCO1B1 variants and statin‐induced myopathy – a genomewide study. The New England Journal of Medicine 359(8): 789–799.

Madian AG, Wheeler HE, Jones RB and Dolan ME (2012) Relating human genetic variation to variation in drug responses. Trends in Genetics: TIG 28(10): 487–495.

Mahgoub A, Idle JR, Dring LG, Lancaster R and Smith RL (1977) Polymorphic hydroxylation of Debrisoquine in man. Lancet 2(8038): 584–586.

Martin MA, Klein TE, Dong BJ et al. (2012) Clinical pharmacogenetics implementation consortium guidelines for hla‐B genotype and abacavir dosing. Clinical Pharmacology and Therapeutics 91(4): 734–738.

Materson BJ, Reda DJ, Cushman WC et al. (1993) Single‐drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. The New England Journal of Medicine 328(13): 914–921.

McCollum AD, Catalano PJ, Haller DG et al. (2002) Outcomes and toxicity in african‐american and caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. Journal of the National Cancer Institute 94(15): 1160–1167.

McCormack M, Alfirevic A, Bourgeois S et al. (2011) HLA‐A*3101 and carbamazepine‐induced hypersensitivity reactions in Europeans. New England Journal of Medicine 364(12): 1134–1143.

Mega JL, Close SL, Wiviott SD et al. (2009) Cytochrome P‐450 polymorphisms and response to clopidogrel. New England Journal of Medicine 360: 354–362.

Mega JL, Hochholzer W, Frelinger AL et al. (2011) Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. Journal of the American Medical Association 306(20): 2221–2228.

Motulsky AG (1957) Drug reactions enzymes, and biochemical genetics. Journal of the American Medical Association 165(7): 835–837.

Nathan DM, Buse JB, Davidson MB et al. (2009) Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52(1): 17–30.

Nickey WA, Lenfant C, Chobanian AV and Roccella EJ (2003) The National High Blood Pressure Education Program: longtime partners with new strategies. The Journal of the American Osteopathic Association 103(6): 297–299.

O'Donnell PH, Bush A, Spitz J et al. (2012) The 1200 patients project: creating a new medical model system for clinical implementation of pharmacogenomics. Clinical Pharmacology and Therapeutics 92(4): 446–449.

Ong FS, Deignan JL, Kuo JZ et al. (2012) Clinical utility of pharmacogenetic biomarkers in cardiovascular therapeutics: a challenge for clinical implementation. Pharmacogenomics 13: 465–475.

Polite BN, Dignam JJ and Olopade OI (2006) Colorectal cancer model of health disparities: understanding mortality differences in minority populations. Journal of Clinical Oncology 24(14): 2179–2187.

Relling MV, Altman RB, Goetz MP and Evans WE (2010) Clinical implementation of pharmacogenomics: Overcoming genetic exceptionalism. Lancet Oncology 11(6): 507–509.

Relling MV and Klein TE (2011) CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clinical Pharmacology and Therapeutics 89(3): 464–467.

Roujeau JC (2005) Clinical heterogeneity of drug hypersensitivity. Toxicology 209(2): 123–129.

Simon T, Verstuyft C, Mary-Krause M et al. (2009) Genetic determinants of response to clopidogrel and cardiovascular events. New England Journal of Medicine 360(4): 363–375.

Stanek EJ, Sanders CL, Taber KA et al. (2012) Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clinical Pharmacology and Therapeutics 91(3): 450–458.

Synder LH (1932) Studies in human inheritance IX. The inheritance of taste deficiency in man. Ohio Journal of Science 32: 436–468.

Takeuchi F, McGinnis R, Bourgeois S et al. (2009) A genome‐wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genetics 5(3): e1000433.

Tantisira KG, Lasky-Su J, Harada M et al. (2011) Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. The New England Journal of Medicine 365(13): 1173–1183.

Taylor AL, Ziesche S, Yancy C et al. (2004) Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. The New England Journal of Medicine 351(20): 2049–2057.

Trevino LR, Shimasaki N, Yang W et al. (2009) Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 27(35): 5972–5978.

Turner ST, Bailey KR, Fridley BL et al. (2008) Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension 52(2): 359–365.

Weinshilboum RM, Raymond FA and Pazmino PA (1978) Human erythrocyte thiopurine methyltransferase: radiochemical microassay and biochemical properties. Clinica Chimica Acta; International Journal of Clinical Chemistry 85(3): 323–333.

Xie HG, Kim RB, Wood AJ and Stein CM (2001) Molecular basis of ethnic differences in drug disposition and response. Annual Review of Pharmacology and Toxicology 41: 815–850.

Yuan HY, Chen JJ, Lee MT et al. (2005) A novel functional VKORC1 promoter polymorphism is associated with inter‐individual and inter‐ethnic differences in warfarin sensitivity. Human Molecular Genetics 14(13): 1745–1751.

Zhou G, Myers R, Li Y et al. (2001) Role of AMP‐activated protein kinase in mechanism of metformin action. The Journal of Clinical Investigation 108(8): 1167–1174.

Zhou K, Bellenguez C, Spencer CC et al. (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics 43(2): 117–120.

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Madian, Ashraf G, and Baker Jones, Richard(Oct 2013) Variable Drug Response: Genetic Evaluation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006001.pub2]