Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges

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Abstract
Serious adverse drug reactions (SADRs) are a significant cause of death. Genetic factors may underlie some of the susceptibility to SADRs. We review three SADRs: drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes with an emphasis on genetic risk factors. Characteristics of SADRs that increase the likelihood of informative genetic/genomic analysis include: evidence for a familial or genetic component, accepted criteria for unambiguous diagnosis, low background incidence and availability of sufficient numbers of cases and appropriately matched controls. Furthermore, information about the molecular mechanisms of drug action and elimination can add to candidate gene and pathway selection and investigation. Clearly defined phenotypes along with standardization of these phenotypes must be in place to ascertain cases and controls and to facilitate replication studies. Networks of scientists and healthcare providers in academia, industry, healthcare systems and regulatory agencies are needed to drive this effort. Effective and standardized procedures for enlisting physician and patient participation in research protocols, collection and transfer of information, DNA, plasma and other specimens must be developed. Confidentiality and ethical issues must be considered in the design and implementation of studies. Study design and the methods for data gathering, storing and analysis must be continually addressed. Replication of findings in diverse population subgroups is important for validating conclusions of these types of studies. For rare SADRs, national and international consortia and networks involving regulatory authorities, health care systems, academic medical centres and industry are crucial for increasing the numbers of cases. Genome-wide association studies may be used to discover new mechanisms responsible for SADRs.