Advertisement

Pharmacogenetics of Idiosyncratic Adverse Drug Reactions

  • Munir PirmohamedEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

Idiosyncratic adverse drug reactions are unpredictable and thought to have an underlying genetic etiology. With the completion of the human genome and HapMap projects, together with the rapid advances in genotyping technologies, we have unprecedented capabilities in identifying genetic predisposing factors for these relatively rare, but serious, reactions. The main roadblock to this is the lack of sufficient numbers of well-characterized samples from patients with such reactions. This is now beginning to be solved through the formation of international consortia, including developing novel ways of identifying and recruiting patients affected by these reactions, both prospectively and retrospectively. This has been led by the research on abacavir hypersensitivity - its association with HLA-B*5701 forms the gold standard of how we need to identify associations and implement them in clinical practice. Strong genetic predisposing factors have also been identified for hypersensitivity reactions such as are associated with carbamazepine, allopurinol, flucloxacillin, and statin-induced myopathy. However, for most other idiosyncratic adverse drug reactions, the genetic effect sizes have been low to moderate, although this may partly be due to the fact that only small numbers have been investigated and limited genotyping strategies have been utilized. It may also indicate that genetic predisposition will be dependent on multiple genes, with complex interactions with environmental factors. Irrespective of the strength of the genetic associations identified with individual idiosyncratic adverse drug reactions, it is important to undertake functional investigations to provide insights into the mechanism(s) of how the drug interacts with the gene variant to lead to a phenotype, which can take a multitude of clinical forms with variable severity. Such investigations will be essential in preventing the burden caused by idiosyncratic reactions, both in healthcare and in industry.

Keywords

Hypersensitivity Pharmacogenetics Drugs HLA Polymorphisms 

Notes

Acknowledgments

The author receives funding from the UK Dept of Health (NHS Chair of Pharmacogenetics program), MRC, and Wellcome Trust.

References

  1. Alfirevic A, Pirmohamed M (2008) Adverse drug reactions and pharmacogenomics: recent advances. Pers Med 5:11-23CrossRefGoogle Scholar
  2. Alfirevic A, Mills T, Harrington P, Pinel T, Sherwood J, Jawaid A, Smith JC, March RE, Chadwick DW, Park BK, Pirmohamed M (2005) Association between serious carbamazepine hypersensitivity reactions and the HSP70 gene cluster. Toxicology 213:264-265Google Scholar
  3. Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M (2006) HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 7:813-818PubMedCrossRefGoogle Scholar
  4. Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598-604PubMedCrossRefGoogle Scholar
  5. Chadwick D, Shaw MDM, Foy P, Rawlins MD, Turnbull DM (1984) Serum anticonvulsant concentration and the drug-induced skin eruptions. J Neurol Neurosurg Psychiatry 47:642-644PubMedCrossRefGoogle Scholar
  6. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT (2004) Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428:486PubMedCrossRefGoogle Scholar
  7. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Peter I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816-819Google Scholar
  8. Edwards SG, Hubbard V, Aylett S, Wren D (1999) Concordance of primary generalised epilepsy and carbamazepine hypersensitivity in monozygotic twins. Postgrad Med J 75:680-681PubMedCrossRefGoogle Scholar
  9. Ford GA, Wood SM, Daly AK (2000) CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system. Br J Clin Pharmacol 50:77-80PubMedCrossRefGoogle Scholar
  10. Gaedigk A, Spielberg SP, Grant DM (1994) Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics 4:142-153PubMedCrossRefGoogle Scholar
  11. Gennis MA, Vemuri R, Burns EA, Hill JV, Miller MA, Spielberg SP (1991) Familial occurrence of hypersensitivity to phenytoin. Am J Med 91:631-634PubMedCrossRefGoogle Scholar
  12. Giacomini KM, Krauss RM, Roden DM, Eichelbaum M, Hayden MR, Nakamura Y (2007) When good drugs go bad. Nature 446:975-977PubMedCrossRefGoogle Scholar
  13. Giezen TJ, Mantel-Teeuwisse AK, Straus SM, Schellekens H, Leufkens HG, Egberts AC (2008) Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA 300:1887-1896PubMedCrossRefGoogle Scholar
  14. Green VJ, Pirmohamed M, Kitteringham NR, Gaedigk A, Grant DM, Boxer M, Burchell B, Park BK (1995) Genetic analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. Biochem Pharmacol 50:1353-1359PubMedCrossRefGoogle Scholar
  15. Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH (2007) The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest 117:3940-3951PubMedGoogle Scholar
  16. Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, Lafon S, Pearce G, Steel H (2001) Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 23:1603-1614PubMedCrossRefGoogle Scholar
  17. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD (2002) Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359:1121-1122PubMedCrossRefGoogle Scholar
  18. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermuller J, Stadler PF, Hartung HP, Berthele A, Deisenhammer F, Wassmuth R, Hemmer B (2008) HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am J Hum Genet 83:219-227PubMedCrossRefGoogle Scholar
  19. Hughes AR, Mosteller M, Bansal AT, Davies K, Haneline SA, Lai EH, Nangle K, Scott T, Spreen WR, Warren LL, Roses AD (2004a) Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics 5:203-211PubMedCrossRefGoogle Scholar
  20. Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M (2004b) Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 14:335-342PubMedCrossRefGoogle Scholar
  21. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT (2005) HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 102:4134-4139PubMedCrossRefGoogle Scholar
  22. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, Hu SL, Wu MT, Chen GS, Wong TW, Hsiao PF, Chen WH, Shih HY, Fang WH, Wei CY, Lou YH, Huang YL, Lin JJ, Chen YT (2006) Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genom 16:297-306CrossRefGoogle Scholar
  23. Jenkins RE, Meng X, Elliot VL, Kitteringham NR, Pirmohamed M, Park BK (2009) Characterisation of flucloxacillin and 5-hydroxymethyl flucloxacillin haptens in vivo. Proteomics 3:720-729Google Scholar
  24. Johnson-Reagan L, Bahna SL (2003) Severe drug rashes in three siblings simultaneously. Allergy 58:445-447PubMedCrossRefGoogle Scholar
  25. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R (2008) HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 9:1617-1622PubMedCrossRefGoogle Scholar
  26. Laaksonen R (2006) On the mechanisms of statin-induced myopathy. Clin Pharmacol Ther 79:529-531PubMedCrossRefGoogle Scholar
  27. Leeder JS (1998) Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs. Epilepsia 39(Suppl 7): S8-S16Google Scholar
  28. Lesko LJ, Woodcock J (2004) Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nat Rev Drug Discov 3:763-769PubMedCrossRefGoogle Scholar
  29. Lindpaintner K (2002) The importance of being modest-reflections on the pharmacogenetics of abacavir. Pharmacogenomics 3:835-838PubMedCrossRefGoogle Scholar
  30. Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy - a genomewide study. N Engl J Med 359:789-799PubMedCrossRefGoogle Scholar
  31. Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, Kangwanshiratada O, Hirankarn N, Suphapeetiporn K, Shotelersuk V (2008) Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 49:2087-2091PubMedCrossRefGoogle Scholar
  32. Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, Graf E, Schumacher M, Hovnanian A, Mockenhaupt M, Roujeau JC (2006) A marker for Stevens-Johnson syndrome...: ethnicity matters. Pharmacogenomics J 6:265-268PubMedGoogle Scholar
  33. Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H, Sakurai M, Sakuma I, Otani H, Sawa H, Kitabatake A (2002) Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 106:1269-1274PubMedCrossRefGoogle Scholar
  34. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 359:727-732PubMedCrossRefGoogle Scholar
  35. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jagel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358:568-579PubMedCrossRefGoogle Scholar
  36. Mank-Seymour AR, Richmond JL, Wood LS, Reynolds JM, Fan YT, Warnes GR, Milos PM, Thompson JF (2006) Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes. Am Heart J 152:1116-1122PubMedCrossRefGoogle Scholar
  37. Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, Carvalho F, Phillips E, Christiansen FT, Purcell AW, McCluskey J, Mallal S (2004) Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 101:4180-4185PubMedCrossRefGoogle Scholar
  38. Marwick C (2003) Bayer is forced to release documents over withdrawal of cerivastatin. BMJ 326:518PubMedCrossRefGoogle Scholar
  39. Mauri-Hellweg D, Bettens F, Mauri D, Brander C, Hunziker T, Pichler WJ (1995) Activation of drug-specific CD4(+) and CD8(+) T-cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 155:462-472PubMedGoogle Scholar
  40. Naisbitt DJ, Pirmohamed M, Park BK (2003) Immunopharmacology of hypersensitivity reactions to drugs. Curr Allergy Asthma Rep 3:22-29PubMedCrossRefGoogle Scholar
  41. Nelson MR, Bacanu SA, Mosteller M, Li L, Bowman CE, Roses AD, Lai EH, Ehm MG (2009) Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions. Pharmacogenomics J 9:23-33PubMedCrossRefGoogle Scholar
  42. Olsson R, Wiholm BE, Sand C, Zettergren L, Hultcrantz R, Myrhed M (1992) Liver damage from flucloxacillin, cloxacillin and dicloxacillin. J Hepatol 15:154-161PubMedCrossRefGoogle Scholar
  43. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82:726-733PubMedCrossRefGoogle Scholar
  44. Pellicano R, Silvestris A, Iannantuono M, Ciavarella G, Lomuto M (1992) Familial occurrence of fixed drug eruptions. Acta Derm Venereol 72:292-293PubMedGoogle Scholar
  45. Peyrieere H, Nicolas J, Siffert M, Demoly P, Hillaire-Buys D, Reynes J (2001) Hypersensitivity related to abacavir in two members of a family. Ann Pharmacother 35:1291-1292PubMedCrossRefGoogle Scholar
  46. Pirmohamed M (2006) Genetic factors in the predisposition to drug-induced hypersensitivity reactions. Aaps J 8:E20-E26PubMedCrossRefGoogle Scholar
  47. Pirmohamed M, Park BK (1996) Mechanisms of hypertransaminemia. In: Cameron RG, Feuer G, de la Iglesia FA (eds) Drug-induced hepatotoxicity. Springer, Berlin, pp 341-366Google Scholar
  48. Pirmohamed M, Park BK (2001) Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci 22:298-305PubMedCrossRefGoogle Scholar
  49. Pirmohamed M, Graham A, Roberts P, Smith D, Chadwick D, Breckenridge AM, Park BK (1991) Carbamazepine hypersensitivity: assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbazepine. Br J Clin Pharmacol 32:741-749PubMedGoogle Scholar
  50. Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK (1998) Fortnightly review - adverse drug reactions. BMJ 316:1295-1298PubMedCrossRefGoogle Scholar
  51. Pirmohamed M, Lin K, Chadwick D, Park BK (2001) TNFalpha promoter region gene polymorphisms in carbamazepine- hypersensitive patients. Neurology 56:890-896PubMedGoogle Scholar
  52. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329:15-19CrossRefGoogle Scholar
  53. Pohl LR, Satoh H, Christ DD, Kenna JG (1988) Immunologic and metabolic basis of drug hypersensitivities. Ann Rev Pharmacol 28:367-387CrossRefGoogle Scholar
  54. Rauch A, Nolan D, Martin A, McKinnon E, 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 43:99-102PubMedCrossRefGoogle Scholar
  55. Rawlins MD, Thompson JW (1991) Mechanisms of adverse drug reactions. In: Davies DM (ed) Textbook of adverse drug reactions. Oxford University Press, Oxford, pp 18-45Google Scholar
  56. Roden DM (2008) Cellular basis of drug-induced torsades de pointes. Br J Pharmacol 154:1502-1507PubMedCrossRefGoogle Scholar
  57. 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 60:76-82PubMedCrossRefGoogle Scholar
  58. Rzany B, Correia O, Kelly JP, Naldi L, Auquier A, Stern R (1999) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study group of the international case control study on severe cutaneous adverse reactions. Lancet 353:2190-2194PubMedCrossRefGoogle Scholar
  59. Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, Stancil B, Mosteller M, Brothers C, Wannamaker P, Hughes A, Sutherland-Phillips D, Mallal S, Shaefer M (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 46:1111-1118PubMedCrossRefGoogle Scholar
  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 22:2025-2033PubMedCrossRefGoogle Scholar
  61. Shear NH, Spielberg SP, Cannon M, Miller M (1988) Anticonvulsant hypersensitivity syndrome: in vitro risk assessment. J Clin Invest 82:1826-1832PubMedCrossRefGoogle Scholar
  62. Strachan DP, Wong HJ, Spector TD (2001) Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins. J Allergy Clin Immunol 108:901-907PubMedCrossRefGoogle Scholar
  63. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018-1028PubMedCrossRefGoogle Scholar
  64. Vittorio CC, Muglia JJ (1995) Anticonvulsant hypersensitivity syndrome. Arch Intern Med 155:2285-2290PubMedCrossRefGoogle Scholar
  65. Wadelius M, Pirmohamed M (2007) Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 7:99-111PubMedCrossRefGoogle Scholar
  66. Waters LJ, Mandalia S, Gazzard B, Nelson M (2007) Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience. AIDS 21:2533-2534Google Scholar
  67. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 447:661-678CrossRefGoogle Scholar
  68. Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM (2007) Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6:904-916PubMedCrossRefGoogle Scholar
  69. Zucman D, Truchis P, Majerholc C, 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 45:1-3PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.MRC Centre for Drug Safety Science, Department of Pharmacology and TherapeuticsThe University of LiverpoolLiverpoolUK

Personalised recommendations