Pharmacogenetics of Adverse Drug Reactions

Abstract

AbstractA large variation in drug response exists between patients, with susceptible individuals being at risk of experiencing an adverse drug reaction (ADR). This susceptibility is attributable to environmental, clinical and genetic factors although the contribution of each varies with the drug, ADR and ethnicity. The variation in drug response makes personalisation of pharmacological therapy appealing to minimise ADRs whilst promoting efficacy. Pharmacogenetics seeks to contribute through genetic-guided drug and dose selection strategies. ADR pharmacogenetics was first highlighted in the 1950s, but it is only in the last decade that it has seen a rapid expansion, aided by significant advances in our knowledge of the human genome and improved genotyping technologies. ADRs can be classified according to whether the dominant mechanism is immune- or nonimmune-mediated. Several ADRs have been strongly associated with specific human leukocyte antigen (HLA) alleles. There is growing evidence for a central role of these alleles in the pathogenesis of immune-mediated delayed hypersensitivity ADRs through facilitation of ‘off-target’ interactions that lead to the presentation of ‘altered self,’ drugs and/or their metabolites to the T-cell receptor in an HLA-restricted fashion. Genetic variation can also predispose to nonimmune-mediated ADRs through perturbing drug pharmacokinetics or by altering nonimmune pharmacodynamic processes. In particular, genetic variants of phase I and phase II biotransformation enzymes and drug transporters alter the availability of a drug at the site(s) responsible for the ADR. Depending on the drug and ADR, these sites may be the therapeutic target site, the same molecular site in another tissue or distinct off-target sites. A prominent example of pharmacogenetics improving drug safety and enhancing the cost-effective use of limited healthcare resources is the reduction in the incidence of the abacavir hypersensitivity syndrome . It is apparent though that the success of ameliorating the abacavir hypersensitivity syndrome by genetic screening is proving difficult to emulate for other drug-ADR combinations. This highlights the considerable hurdles encountered in translating a pharmacogenetic association into a clinical test that benefits patient safety. The development of international consortia alongside the potential of next generation sequencing technologies and other innovations offer tantalising prospects for future advances in pharmacogenetics to reduce the burden of ADRs.KeywordsAdverse drug reactionPharmacogeneticsPredictive genotypingTranslationAbacavirHypersensitivityMalignant hyperthermiaCodeineWarfarinStatin