Review
Genetic susceptibility to adverse drug reactions

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Abstract

Adverse drug reactions (ADRs) are a major clinical problem. Genetic factors can determine individual susceptibility to both dose-dependent and dose-independent ADRs. Determinants of susceptibility include kinetic factors, such as gene polymorphisms in cytochrome P450 enzymes, and dynamic factors, such as polymorphisms in drug targets. The relative importance of these factors will depend on the nature of the ADR; however, it is likely that more than one gene will be involved in most instances. In the future, whole genome single nucleotide polymorphism (SNP) profiling might allow an unbiased method of determining genetic predisposing factors for ADRs, but might be limited by the lack of adequate numbers of patient samples. The overall clinical utility of genotyping in preventing ADRs needs to be proven by the use of prospective randomized controlled clinical trials.

Section snippets

Classification of adverse drug reactions

From a clinical perspective, ADRs can be divided into two broad types, type A and type B (Ref. 10) (Table 1). Type A reactions are predictable from the known pharmacology of the drug and often represent an exaggeration of the known primary and/or secondary pharmacology of the drug. By contrast, type B ADRs are bizarre reactions that are unpredictable from the known pharmacology of the drug and show no apparent dose–response relationship 11. Typically, type A ADRs have been labelled as host

Genetic polymorphisms and adverse drug reactions

A gene can be defined as exhibiting a genetic polymorphism if the variant allele exists in the normal population at a frequency of at least 1% (Ref. 13). Genetic polymorphisms are a source of variation of drug response in the human body. In relation to ADRs, most interest has centred on the involvement of pharmacokinetic factors and, in particular, drug metabolism. However, there is now increasing realization that genetic variation in drug targets (pharmacodynamic factors) might also predispose

Phase I metabolic pathways

Several polymorphisms that affect genes encoding cytochrome P450 enzymes have been described (Table 2), although polymorphisms in the gene encoding CYP2D6 have attracted most attention. This P450 isoform is responsible for the metabolism of ∼25% of drugs, including certain antidepressants, antipsychotics, β-blockers and opioid analgesics. Variability in the rate of drug metabolism by CYP2D6 is >100-fold; this is genetically determined with 6% of the caucasian population carrying two null

Phase II metabolic pathways

Many Phase II drug metabolizing enzymes have been shown to be polymorphically expressed (Table 3), which in turn has led to the occurrence of ADRs with several drugs. N-acetyltransferase type 2 (NAT-2) was one of the first Phase II enzymes discovered to be polymorphically expressed 36. However, largely for the same reasons outlined for CYP2D6 above, patients are not routinely typed for NAT-2 before starting drug therapy. The glutathione-S-transferase enzyme gene polymorphisms, although of

Transporters

Membrane transporters play an important role in the absorption, distribution and excretion of drugs. A large number of transporters have now been described, which should be a fruitful area for future research into the causes of variability in drug response. To date, most studies have focused on the multi-drug resistance gene (ABCB1), which encodes P-glycoprotein (Pgp), an efflux pump with wide substrate specificity that has been implicated in resistance to anti-tumour agents 57. A recent study

G6PD

Genetically determined variation in enzyme structure might render the enzyme more sensitive to the action of a drug, resulting in toxicity (Table 4). The archetypal example is G6PD deficiency, a sex-linked disorder that affects ∼200 million people worldwide 60. The incidence and severity of the enzyme deficiency vary with race, which reflects the large number (∼400) of variants that have been described. In the majority of individuals, the deficiency causes haemolysis only in the presence of

Receptors

The therapeutic response to a drug acting on a receptor might be modulated by genetic variation in that receptor as has been shown for β2-adrenoceptor agonists 62 and antipsychotics such as clozapine 63. However, such variation might also increase the sensitivity of that receptor and lead to adverse effects. For example, a serine to glycine substitution in the gene encoding the dopamine D3 receptor has recently been shown to predispose to the occurrence of tardive dyskinesia following treatment

Ion channels

Recently, the use of several drugs including terfenadine, cisapride, thioridazine and sertindole has been restricted because of the occurrence of QT-interval prolongation on the electrocardiogram (ECG) and occasionally torsades de pointes (TdP) 66. Mutations in various ion channels that are responsible for normal ventricular repolarization have been reported in patients with inherited long-QT syndromes 67. All drugs that are known to cause prolongation of the QT interval preferentially block

Immune response genes

Approximately 20% of all ADRs are thought to have an immunological aetiology 70, and are categorized as type B ADRs (Table 1; although it is important to remember that not all type B reactions are immune mediated). Bioactivation of drugs to chemically reactive intermediates that act as haptens is important in the pathogenesis of these ADRs (Ref. 11). Predisposition to such ADRs is thought to be multi-factorial, involving many genes that interact with environmental factors 12. In a similar

Future perspectives and conclusions

The current approach to the identification of genetic predisposition to ADRs is limited by our knowledge of the mechanisms of the ADR, and thus our restricted choice of candidate genes. An alternative strategy is to use a comprehensive, densely spaced, genome-wide SNP map, which might allow us in the future to conduct screens for pharmacogenetically active genes as whole-genome, unbiased searches 84. SNPs are single-base differences in the DNA sequence, observed between individuals, which occur

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