Adverse drug reactions (ADRs) represent a major public health problem. A meta-analysis by Lazarou et al. (1), based mainly on studies conducted before 1990, showed that 6.7% of hospitalized patients developed serious ADRs, while 0.32% had a fatal ADR. Extrapolation of the fatality rate to the population of the United States suggested that ADRs killed more than 100,000 patients in the United States in 1994, making them between the fourth and sixth leading cause of death. In one of the largest prospective studies ever conducted, we have shown that even with present-day therapeutics, ADRs are responsible for 6.5% of all hospital admissions, accounting for 4% of the National Health Service (NHS) hospital bed occupancy at an annual cost approaching £0.5 billion (2). In children, the overall incidence of ADRs may be as high as 9.5% (3) although larger prospective studies are desperately needed in this area. The overall cost of drug-related morbidity and mortality in the United States (taking into account both primary and secondary care) has been estimated to be more than $76 billion (4). There are also cost implications for the pharmaceutical industry: the cost of bringing a drug to the market has been estimated to be up to $800 million (5). It has been estimated that up to 4% of the drugs marketed in the United Kingdom over a 20-year period were withdrawn because of safety issues (6).

Many factors contribute to the occurrence of ADRs. Prominent amidst this is poor prescribing behavior, for example, prescribing inappropriate doses in the presence of a contraindication or coprescribing of two drugs with a potential for interaction. However, even when such "environmental" factors are removed, a significant proportion of ADRs may occur because of genetic predisposition. Additionally, there may be an interaction between environmental and genetic factors that may also predispose to the development of an ADR. The overall contribution of host or genetic factors to the occurrence of ADRs is not clear. In order to address this issue, at least partially, a systematic review attempted to quantitate the role of polymorphisms in cytochrome P450 enzyme genes in predisposing to adverse drug reactions (7). Of the 27 drugs most frequently cited in ADR studies, 59% were metabolized by at least one enzyme with a variant allele associated with reduced activity, compared with 7% to 22% of the randomly selected drugs.

CYP1A2 and CYP2D6, which metabolize 5% and 25% of all prescribed drugs (8), respectively, were implicated in metabolizing 75% and 38% of the ADR drugs. This provides circumstantial evidence that dose alteration through knowledge of the patient's genotype may have prevented some of these ADRs. However, it is important to note that the design of the study (relating published ADR studies with review articles of drug metabolizing enzyme gene polymorphisms) shows an association and not causation, and it does not take into account the fact that ADRs can be polygenic and multifactorial in predisposition.

In this chapter, we review the evidence relating to the occurrence of ADRs to genetic factors, starting with a historical overview, and ending with socioeconomic perspectives.

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