PHARMACOGENETICS: CURRENT STATUS, FUTURE CHALLENGES Prof. Munir Pirmohamed, United Kingdom    - Biography English - 2007-10-08

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Pharmacogenetics is the study of how genetic variation determines individual drug response. The term was coined in 1957, almost 50 years ago. Despite the long history, pharmacogenetics has made little clinical impact, bar a few exceptions, for example TPMT and 6-mercaptopurineinduced leucopenia. Most of the associations with genetic polymorphisms are largely ignored by clinicians who continue prescribing regardless of individual genetic constitution. The human genome project has spurred on research in pharmacogenetics and it is vitally important that the opportunity for translation into clinical practice is not lost and we do not repeat the mistakes of the last half century. The research community, as a whole, now has access to a wealth of data regarding human variation. The challenge lies in relating the genome variation data to individual variation in drug response. Success will depend on ensuring that the drug response phenotype is accurate. Accurate definition of the phenotype is one of the areas that have been poorly undertaken in many previous studies resulting in non-replication of positive findings, contradictory data in the literature, and confusion amongst prescribers, and thereby, lack of translation into clinical practice. More prospective study designs which allow an assessment of environmental contributors, as well as genetic factors, need to be undertaken. Such studies need to be adequately powered and will be more expensive than the usual case-control studies that have been undertaken so far, but their initial expense is likely to be off-set by the generation of data that will show clinical validity and clinical utility. Another factor that has contributed to the lack of clinical implementation is that we have underestimated the complexity of the drug response phenotype. It is likely that most drug response phenotypes (efficacy or toxicity) will be determined by multiple genes interacting with environmental factors. Any genotyping strategy therefore has to be comprehensive taking into account the diversity within the gene (using haplotype mapping techniques) and within all the genes in the whole drug response pathway. Apart from the above, many other factors need to be taken into account when assessing the clinical implementation of a pharmacogenetic predictor, including cost effectiveness, patient and clinical acceptability, ethical issues, the testing infrastructure in a healthcare setting and knowledge about pharmacogenetics. It is important we adopt a comprehensive strategy which spans the whole spectrum from the laboratory to the patient bedside, and in addition takes into account societal factors. Without such an approach, the clinical translation of pharmacogenetics will be patchy and haphazard.