Genetics of Immune-Mediated Adverse Drug Reactions: a Comprehensive and Clinical Review



Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug-induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future.


Adverse drug reactions Drug-induced skin injury Drug-induced liver injury Human leukocyte antigen Maculopapular exanthema Hypersensitivity syndrome Stevens-Johnson syndrome Hypersensitivity Abacavir Allopurinol Carbamazepine Flucloxacillin Ximelagatran 



Vincent Yip is a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Grant Number G1000417), ICON, GlaxoSmithKline, AstraZeneca, and the Medical Evaluation Unit.


  1. 1.
    Aronson JK, Ferner RE (2005) Clarification of terminology in drug safety. Drug Saf 28(10):851–870PubMedGoogle Scholar
  2. 2.
    Pirmohamed M, James S, Meakin S et al (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients. BMJ: Br Med J 7456:15–19Google Scholar
  3. 3.
    Davies EC, Mottram DR, Green CF, Taylor S, Williamson PR, Pirmohamed M (2009) Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS ONE 4(2):e4439PubMedCentralPubMedGoogle Scholar
  4. 4.
    Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA J Am Med Assoc 279(15):1200–1205Google Scholar
  5. 5.
    FDA Centre for Drug Evaluation and Research (2005) Report to the Nation 2005: Improving Public Health through Drugs. Accessed 14 Jan 2013
  6. 6.
    Rawlins M, Thompson J (1991) Mechanisms of adverse drug reactions. In Textbook of Adverse Drug Reactions. Oxford University Press, OxfordGoogle Scholar
  7. 7.
    Pirmohamed M (2012) Genetics and the potential for predictive tests in adverse drug reactions. Chem Immunol Allergy 97:18–31PubMedGoogle Scholar
  8. 8.
    Mallal S, Nolan D, Witt C et al (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359(9308):727–732PubMedGoogle Scholar
  9. 9.
    Chung W-H, Hung S-I, Hong H-S et al (2004) Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428(6982):486–486PubMedGoogle Scholar
  10. 10.
    McCormack M, Alfirevic A, Bourgeois S et al (2011) HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 364(12):1134–1143PubMedCentralPubMedGoogle Scholar
  11. 11.
    Hautekeete ML, Horsmans Y, Van Waeyenberge C et al (1999) HLA association of amoxicillin-clavulanate-induced hepatitis. Gastroenterology 117(5):1181–1186PubMedGoogle Scholar
  12. 12.
    Becquemont L (2010) HLA: a pharmacogenomics success story. Pharmacogenomics 11(3):277–281PubMedGoogle Scholar
  13. 13.
    Pirmohamed M, Aithal GP, Behr E, Daly A, Roden D (2011) The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions. Clin Pharmacol Ther 89(6):784–785PubMedGoogle Scholar
  14. 14.
    Pirmohamed M, Friedmann PS, Molokhia M et al (2011) Phenotype standardization for immune-mediated drug-induced skin injury. Clin Pharmacol Ther 89(6):896–901PubMedGoogle Scholar
  15. 15.
    Aithal GP, Watkins PB, Andrade RJ et al (2011) Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 89(6):806–815PubMedGoogle Scholar
  16. 16.
    Pirmohamed M, Park BK (2001) Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci 22(6):298–305PubMedGoogle Scholar
  17. 17.
    Alfirevic A, Pirmohamed M (2010) Drug-induced hypersensitivity reactions and pharmacogenomics: past, present and future. Pharmacogenomics 11(4):497–499PubMedGoogle Scholar
  18. 18.
    Roujeau J-C, Kelly JP, Naldi L et al (1995) Medication use and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333(24):1600–1608PubMedGoogle Scholar
  19. 19.
    Hetherington S, Hughes AR, Mosteller M et al (2002) Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359(9312):1121–1122PubMedGoogle Scholar
  20. 20.
    Hughes D, Vilar F, Ward C, Alfirevic A, Park BK, Pirmohamed M (2004) Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 14:335–342PubMedGoogle Scholar
  21. 21.
    Mallal S, Phillips E, Nolan D et al (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358(6):568–579PubMedGoogle Scholar
  22. 22.
    Saag M, Balu R, Phillips E et al (2008) High sensitivity of human leukocyte antigen-B*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 46(7):1111–1118PubMedGoogle Scholar
  23. 23.
    Man CBL, Kwan P, Baum L et al (2007) Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 48(5):1015–1018PubMedGoogle Scholar
  24. 24.
    Wu XT, Hu FY, An DM et al (2010) Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B*1502 allele among patients in central China. Epilepsy Behav 19(3):405–408PubMedGoogle Scholar
  25. 25.
    Wang Q, Zhou J-Q, Zhou L-M et al (2011) Association between HLA-B*1502 allele and carbamazepine-induced severe cutaneous adverse reactions in Han people of southern China mainland. Seizure 20(6):446–448PubMedGoogle Scholar
  26. 26.
    Hung S-I, Chung W-H, Jee S-H et al (2006) Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 16(4):297–306PubMedGoogle Scholar
  27. 27.
    Tassaneeyakul W, Tiamkao S, Jantararoungtong T et al (2010) Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population. Epilepsia 51(5):926–930PubMedGoogle Scholar
  28. 28.
    Locharernkul C, Loplumlert J, Limotai C et al (2008) Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 49(12):2087–2091PubMedGoogle Scholar
  29. 29.
    Then SM, Rani ZZM, Raymond AA, Ratnaningrum S, Jamal R (2011) Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients. Asian Pac J Allergy Immunol 29(3):290–293PubMedGoogle Scholar
  30. 30.
    Mehta TY, Prajapati LM, Mittal B et al (2009) Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol 75(6):579–582PubMedGoogle Scholar
  31. 31.
    Ozeki T, Mushiroda T, Yowang A et al (2011) Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet 20(5):1034–1041PubMedGoogle Scholar
  32. 32.
    Kim S-H, Lee KW, Song W-J et al (2011) Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res 97(1–2):190–197PubMedGoogle Scholar
  33. 33.
    Hung S-I, Chung W-H, Liou L-B et al (2005) HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 102(11):4134–4139PubMedCentralPubMedGoogle Scholar
  34. 34.
    Tassaneeyakul W, Jantararoungtong T, Vannaprasaht S et al (2009) Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 19(9):704–709PubMedGoogle Scholar
  35. 35.
    Kaniwa N, Saito Y, Aihara M et al (2008) HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 9(11):1617–1622PubMedGoogle Scholar
  36. 36.
    Ding WY, Lee CK, Choon SE et al (2010) Cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol 49(7):834PubMedGoogle Scholar
  37. 37.
    Kazeem GR, Cox C, Aponte J et al (2009) High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients. Pharmacogenet Genomics 19(9):661PubMedGoogle Scholar
  38. 38.
    Martin AM, Nolan D, James I et al (2005) Predisposition to nevirapine hypersensitivity associated with HLA-DRB1 0101 and abrogated by low CD4 T-cell counts. AIDS 19(1):97PubMedGoogle Scholar
  39. 39.
    Vitezica ZG, Milpied B, Lonjou C et al (2008) HLA-DRB1 01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. AIDS 22(4):540PubMedGoogle Scholar
  40. 40.
    Littera R, Carcassi C, Masala A et al (2006) HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients. AIDS 20(12):1621PubMedGoogle Scholar
  41. 41.
    Gatanaga H, Yazaki H, Tanuma J et al (2007) HLA-Cw8 primarily associated with hypersensitivity to nevirapine. AIDS 21(2):264PubMedGoogle Scholar
  42. 42.
    Chantarangsu S, Mushiroda T, Mahasirimongkol S et al (2009) HLA-B 3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genomics 19(2):139PubMedGoogle Scholar
  43. 43.
    Umapathy S, Pawar A, Bajpai S, Pazare AR, Ghosh K (2011) HLA involvement in nevirapine-induced dermatological reaction in antiretroviral-treated HIV-1 patients. J Pharmacol Pharmacother 2(2):114–115PubMedCentralPubMedGoogle Scholar
  44. 44.
    Likanonsakul S, Rattanatham T, Feangvad S et al (2009) HLA-Cw*04 allele associated with nevirapine-induced rash in HIV-infected Thai patients. AIDS Res Ther 6:22PubMedCentralPubMedGoogle Scholar
  45. 45.
    Gao S, Gui X-E, Liang K et al (2012) HLA-dependent hypersensitivity reaction to nevirapine in Chinese Han HIV-infected patients. AIDS Res Hum Retrovir 28(6):540PubMedGoogle Scholar
  46. 46.
    Lonjou C, Borot N, Ledger N et al (2008) A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 18(2):99–107PubMedGoogle Scholar
  47. 47.
    Roujeau J-C, Bracq C, Huyn NT, Chaussalet E, Raffin C, Duédari N (1986) HLA phenotypes and bullous cutaneous reactions to drugs. Tissue Antigens 28(4):251–254PubMedGoogle Scholar
  48. 48.
    Romano A, Fonso MD, Venuti A et al (1998) Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes. Ann Allergy Asthma Immunol 80(5):433–437PubMedGoogle Scholar
  49. 49.
    Özkaya-Bayazit E, Akar U (2001) Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. J Am Acad Dermatol 45(5):712–717PubMedGoogle Scholar
  50. 50.
    Hetherington S, McGuirk S, Powell G et al (2001) Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 23(10):1603–1614PubMedGoogle Scholar
  51. 51.
    Phillips EJ, Sullivan JR, Knowles SR, Shear NH (2002) Utility of patch testing in patients with hypersensitivity syndromes associated with abacavir. AIDS 16(16):2223–2225PubMedGoogle Scholar
  52. 52.
    Symonds W, Cutrell A, Edwards M et al (2002) Risk factor analysis of hypersensitivity reactions to abacavir. Clin Ther 24(4):565–573PubMedGoogle Scholar
  53. 53.
    Peyrieère H et al (2001) Hypersensitivity related to abacavir in two members of a family. Ann Pharmacother 35(10):1291PubMedGoogle Scholar
  54. 54.
    Nolan D, Martin A, Almeida C, Mallal S (2006) Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 43(1):99–102PubMedGoogle Scholar
  55. 55.
    Waters LJ, Mandalia S, Gazzard B, Nelson M (2007) Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience. AIDS 21(18):2533–2534PubMedGoogle Scholar
  56. 56.
    Zucman D, Majerholc C, Truchis PD, Stegman S, Caillat-Zucman S (2007) Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. J Acquir Immune Defic Syndr 45(1):1–3PubMedGoogle Scholar
  57. 57.
    Colombo S, Rotger M, Martinez R et al (2008) The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir. J Infect Dis 198(6):864–867PubMedGoogle Scholar
  58. 58.
    Dello Russo C, Lisi L, Lofaro A et al (2011) Novel sensitive, specific and rapid pharmacogenomic test for the prediction of abacavir hypersensitivity reaction: HLA-B*57:01 detection by real-time PCR. Pharmacogenomics 12(4):567–576PubMedGoogle Scholar
  59. 59.
    Kauf TL, Farkouh RA, Earnshaw SR, Watson ME, Maroudas P, Chambers MG (2010) Economic efficiency of genetic screening to inform the use of abacavir sulfate in the treatment of HIV. PharmacoEconomics 28(11):1025–1039PubMedGoogle Scholar
  60. 60.
    Schackman BR, Scott CA, Walensky RP, Losina E, Freedberg KA, Sax PE (2008) The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV. AIDS 22(15):2025–2033PubMedCentralPubMedGoogle Scholar
  61. 61.
    Marson AG, Al-Kharusi AM, Alwaidh M et al (2007) The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 369(9566):1000–1015PubMedCentralPubMedGoogle Scholar
  62. 62.
    Post RM, Ketter TA, Uhde T, Ballenger JC (2007) Thirty years of clinical experience with carbamazepine in the treatment of bipolar illness: principles and practice. CNS Drugs 21(1):47–71PubMedGoogle Scholar
  63. 63.
    Cruccu G, Gronseth G, Alksne J et al (2008) AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol Off J Eur Fed Neurol Soc 15(10):1013–1028Google Scholar
  64. 64.
    Wu Y, Farrell J, Pirmohamed M, Park BK, Naisbitt DJ (2007) Generation and characterization of antigen-specific CD4+, CD8+, and CD4 + CD8+ T-cell clones from patients with carbamazepine hypersensitivity. J Allergy Clin Immunol 119(4):973–981PubMedGoogle Scholar
  65. 65.
    Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M (2006) HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 7(6):813–818PubMedGoogle Scholar
  66. 66.
    Lonjou C, Thomas L, Borot N et al (2006) A marker for Stevens-Johnson syndrome: ethnicity matters. Pharmacogenomics J 6(4):265–268PubMedGoogle Scholar
  67. 67.
    Kano Y, Hirahara K, Asano Y, Shiohara T (2008) HLA-B allele associations with certain drugs are not confirmed in Japanese patients with severe cutaneous drug reactions. Acta Derm Venereol 88(6):616–618PubMedGoogle Scholar
  68. 68.
    Lim KS, Tan CT, Kwan P (2008) Association of HLA-B*1502 allele and carbamazepine-induced severe adverse cutaneous drug reaction among Asians, a review. Neurol Asia 13:15–21Google Scholar
  69. 69.
    Yip VL, Marson AG, Jorgensen AL, Pirmohamed M, Alfirevic A (2012) HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review. Clin Pharmacol Ther 92(6):757–765PubMedGoogle Scholar
  70. 70.
    Chen P, Lin J-J, Lu C-S et al (2011) Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 364(12):1126–1133PubMedGoogle Scholar
  71. 71.
    Locharernkul C, Shotelersuk V, Hirankarn N (2010) HLA-B* 1502 screening: time to clinical practice. Epilepsia 51(5):936–938PubMedGoogle Scholar
  72. 72.
    Ferrell PB, McLeod HL (2008) Carbamazepine, HLA-B*1502 and risk of Stevens–Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 9(10):1543–1546PubMedCentralPubMedGoogle Scholar
  73. 73.
    Kang HR, Kim YS, Jung JW et al (2011) Positive and negative associations of HLA class i alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics 21(5):303–307PubMedGoogle Scholar
  74. 74.
    Ostapowicz G, Fontana RJ, Schiødt FV et al (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137(12):947–954PubMedGoogle Scholar
  75. 75.
    Sgro C, Clinard F, Ouazir K et al (2002) Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 36(2):451–455PubMedGoogle Scholar
  76. 76.
    Björnsson E, Jerlstad P, Olsson R, Bergqvist A (2005) Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 40(9):1095–1101PubMedGoogle Scholar
  77. 77.
    Temple R (2006) Hepatotoxicity through the years. Accessed 23 Jan 2013
  78. 78.
    Russmann S, Kullak-Ublick GA, Grattagliano I (2009) Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 16(23):3041–3053PubMedCentralPubMedGoogle Scholar
  79. 79.
    O’Donohue J, Mills PR, Oien KA et al (2000) Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 47(5):717–720PubMedCentralPubMedGoogle Scholar
  80. 80.
    Donaldson PT, Daly AK, Henderson J et al (2010) Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury. J Hepatol 53(6):1049–1053PubMedGoogle Scholar
  81. 81.
    Lucena MI, Andrade RJ, Stephens C et al (2011) Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class i and II alleles. Gastroenterology 141(1):338–347PubMedCentralPubMedGoogle Scholar
  82. 82.
    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. Nat Genet 41(7):816–819PubMedGoogle Scholar
  83. 83.
    Kindmark A, Jawaid A, Harbron CG et al (2008) Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 8(3):186–195PubMedGoogle Scholar
  84. 84.
    Singer JB, Lewitzky S, Leroy E et al (2010) A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 42(8):711–714PubMedGoogle Scholar
  85. 85.
    Yuan J, Guo S, Huang Z et al (2011) Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS 25(10):1271–1280PubMedCentralPubMedGoogle Scholar
  86. 86.
    Spraggs CF, Budde LR, Briley LP et al (2011) HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 29(6):667–673PubMedGoogle Scholar
  87. 87.
    Hirata K, Yamamoto M, Okutani Y et al (2008) Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study. Pharmacogenomics J 8(1):29–33PubMedGoogle Scholar
  88. 88.
    Ariyoshi N, Iga Y, Hirata K et al (2010) Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese. Drug Metab Pharmacokinet 25(3):298PubMedGoogle Scholar
  89. 89.
    Andrade RJ, García-Ruiz E, García-Muñoz B et al (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129(2):512–521PubMedGoogle Scholar
  90. 90.
    Chalasani N, Fontana RJ, Bonkovsky HL et al (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135(6):1924–1934, e1924PubMedCentralPubMedGoogle Scholar
  91. 91.
    García Rodríguez LA, Stricker BH, Zimmerman HJ (1996) Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Med 156(12):1327–1332PubMedGoogle Scholar
  92. 92.
    Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM (2005) Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 50(10):1785–1790PubMedGoogle Scholar
  93. 93.
    Andrade RJ, Lucena MI, Alonso A et al (2004) HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology (Baltimore, Md) 39(6):1603–1612Google Scholar
  94. 94.
    Russmann S, Kaye JA, Jick SS, Jick H (2005) Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database. Br J Clin Pharmacol 60(1):76–82PubMedCentralPubMedGoogle Scholar
  95. 95.
    Alfirevic A, Pirmohamed M (2012) Predictive genetic testing for drug-induced liver injury: considerations of clinical utility. Clin Pharmacol Ther 92(3):376–380PubMedGoogle Scholar
  96. 96.
    Testa L, Bhindi R, Van Gaal WJ, Agostoni P, Abbate A, Biondi Zoccai GGL (2007) The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile. Expert Opin Drug Saf 6(4):397–406PubMedGoogle Scholar
  97. 97.
    Bonierbale E, Valadon P, Pons C et al (1999) Opposite behaviors of reactive metabolites of tienilic acid and its isomer toward liver proteins: use of specific anti-tienilic acid & minus; protein adduct antibodies and the possible relationship with different hepatotoxic effects of the two compounds. Chem Res Toxicol 12(3):286PubMedGoogle Scholar
  98. 98.
    Aithal GP, Rawlins MD, Day CP (1999) Accuracy of hepatic adverse drug reaction reporting in one English health region. BMJ (Clin Res Ed) 319(7224):1541Google Scholar
  99. 99.
    Rockey DC, Seeff LB, Rochon J et al (2010) Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method. Hepatology 51(6):2117–2126PubMedCentralPubMedGoogle Scholar
  100. 100.
    Chessman D, Kostenko L, Lethborg T et al (2008) Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28(6):822PubMedGoogle Scholar
  101. 101.
    Alfirevic A, Gonzalez-Galarza F, Bell C et al (2012) In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers. Genome Med 4(6):51PubMedCentralPubMedGoogle Scholar
  102. 102.
    Evans WE (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 26(2):186–191PubMedGoogle Scholar
  103. 103.
    Lindh JD, Holm L, Andersson ML et al (2009) Influence of CYP2C9 genotype on warfarin dose requirements—a systematic review and meta-analysis. Eur J Clin Pharmacol 65(4):365PubMedGoogle Scholar
  104. 104.
    Innocenti F, Undevia SD, Iyer L et al (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22(8):1382–1388PubMedGoogle Scholar
  105. 105.
    Youngster I, Arcavi L, Schechmaster R et al (2010) Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf 33(9):713PubMedGoogle Scholar
  106. 106.
    Brugts JJ, Isaacs A, Boersma E et al (2010) Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease. Eur Heart J 31(15):1854PubMedGoogle Scholar
  107. 107.
    Veenstra D, Higashi M, Phillips K, Veenstra DL, Higashi MK, Phillips KA (2000) Assessing the cost-effectiveness of pharmacogenomics. AAPS PharmSci 2(3):80PubMedCentralGoogle Scholar
  108. 108.
    Bodmer W, Bonilla C, Bodmer W et al (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40(6):695PubMedCentralPubMedGoogle Scholar
  109. 109.
    Szyf M, Szyf M, Szyf M (2007) The dynamic epigenome and its implications in toxicology. Toxicol Sci 100(1):7PubMedGoogle Scholar
  110. 110.
    Kacevska M, Ivanov M, Ingelman-Sundberg M (2011) Perspectives on epigenetics and its relevance to adverse drug reactions. Clin Pharmacol Ther 89(6):902–907PubMedGoogle Scholar
  111. 111.
    Pirmohamed M (2010) Acceptance of biomarker-based tests for application in clinical practice: criteria and obstacles. Clin Pharmacol Ther 88(6):862–866PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Molecular and Clinical PharmacologyThe University of Liverpool, The Wolfson Centre for Personalised MedicinesLiverpoolUK

Personalised recommendations