Genetics of Adverse Drug Reactions

Abstract

Adverse drug reactions (ADRs) remain a common and a major problem in healthcare. Many kinds of ADRs are predictable, dose‐dependent and associated with the pharmacodynamic and pharmacokinetic of drugs. However, some are unpredictable, dose‐independent and termed as idiosyncratic reactions. A number of recent studies have demonstrated that ADRs possess strong genetic predisposition, and the associated risk variants include HLA alleles [e.g. HLA‐B*15:02 for carbamazepine‐induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), HLA‐B*58:01 for allopurinol‐induced SJS/TEN and HLA‐B*57:01 for abacavir hypersensitivity], drug‐metabolising enzymes (e.g. CYP2C9*3 for phenytoin‐induced severe cutaneous adverse reactions and NUDP15 missense variants for thiopurine‐induced leukopenia) and drug transporters (e.g. SLCO1B1 variants for statin‐induced myopathy). These findings not only give insights into the pathogenesis of ADRs but also lead to the development of useful tests to reduce the incidences of ADRs.

Key Concepts

  • ADRs possess strong genetic predisposition, and the identified important risk factors include genes encoding human leukocyte antigens (HLA), drug‐metabolising enzymes and drug transporters.
  • The human HLA alleles are highly polymorphic and associated with different types of ADRs, including cutaneous adverse reactions and drug‐induced liver injury. The association has characteristics of drug‐, ethnic‐ and phenotype‐specificity.
  • The human HLA alleles exhibit strong association with severe cutaneous adverse reactions, for example, HLA‐B*15:02 and carbamazepine‐induced SJS/TEN, HLA‐B*58:01 and allopurinol‐induced SJS/TEN/DRESS and HLA‐B*57:01 and abacavir hypersensitivity.
  • Polymorphisms of cytochromes P450 (e.g. CYP2D6, CYP2C9 and CYP2C19) and other drug‐metabolising enzymes (e.g. glucose‐6‐phosphate dehydrogenase and nucleoside diphosphate linked moiety X‐type motif 15) can cause defective or altered enzyme activity, and are associated with different kinds of ADRs.
  • The genetic alterations of drug transporters (e.g. ATP‐binding cassette (ABC) and solute carrier (SLC) transporters) are also linked to ADRs.
  • The epigenetic effects on drug‐metabolising enzymes and drug transporters may also contribute to the individual susceptibility to ADRs.
  • Implementation of the genetic screen before drug prescription has been applied in clinical practice, and these pharmacogenetic tests show efficacy for preventing ADRs.

Keywords: adverse drug reactions; CYP; drug‐metabolising enzymes; drug transporters; genetics; HLA; pharmacogenomics

Figure 1. Genetic factors involved in the pathomechanism of adverse drug reactions. The genetic polymorphisms of drug‐metabolising enzymes or drug transporters can cause the increase of drug/toxic metabolites in human body. The drug itself or the produced metabolite can serve as a foreign antigen and trigger immune response through HLA presentation and TCR recognition, resulting in the development of adverse reactions (e.g. skin injury or organ damage). Abbreviations: ABC, ATP‐binding cassette; APC, antigen‐presenting cell; CYP, cytochromes P450; G6PD, glucose‐6‐phosphate dehydrogenase; HLA, human leukocyte antigen; NUDT15, nucleoside diphosphate linked moiety X‐type motif 15; UGT1A1, uridine diphospho glucuronosyltransferase 1A1; SLCO1B1, solute carrier organic anion transporter family, member 1B1; TCR, T‐cell receptor.
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Wang, Chuang‐Wei, Chung, Wen‐Hung, and Hung, Shuen‐Iu(Jan 2017) Genetics of Adverse Drug Reactions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024914]