Genetic factors in the predisposition to drug-induced hypersensitivity reactions

Abstract

Drug hypersensitivity reactions can occur with most drugs, although the frequency, severity, and clinical manifestations vary. Case reports have suggested that there may be familial clustering of drug hypersensitivity suggesting a genetic predisposition. As with most other forms of drug response, predisposition to drug hypersensitivity reactions is likely to be multifactorial and multigenic. Given the immune pathogenesis of these reactions, it is perhaps not surprising that the most significant genetic associations have been identified in the major histocompatibility complex for drugs such as abacavir, carbamazepine, and allopurinol. For abacavir, it has been suggested that preprescription genotyping for HLA-B*5701 in whites may reduce the incidence of hypersensitivity. It is likely that as our knowledge of variation in the human genome improves, coupled with improvements in technology, many more significant genetic predisposing factors for drug hypersensitivity are likely to be identified in the next decade. However, as we search for these genetic factors, it is important that we do not forget environmental predisposition, and to bear in mind that a genetic marker for drug hypersensitivity in one population may not necessarily be relevant for another population. Notwithstanding the advances in genetic technologies, the ultimate determinant of success in this area of research will be the identification and careful phenotyping of patients with drug hypersensitivity reactions. As we progress to whole genome scanning, in order to satisfy the requirements for adequate statistical power, the identification of large numbers of carefully phenotyped patients will be feasible only through international collaborations.