Genetics of the adverse drug reaction
ADRs often lead to poor compliance and discontinuation of vital therapies, and represent one of the leading causes of death in hospitalised patients. Current knowledge of the possible genetic predisposition for ADRs is limited. The EU-funded PREDICTON-ADR consortium of European scientists investigated the genetic basis of muscle damage and angioedema resulting from drugs that are used to manage cardiovascular risk. The primary focus of PREDICTION-ADR was on the ADRs in two commonly prescribed drug classes: statins and angiotensin-converting enzyme inhibitors (ACEIs). The goal was to optimise the management of cardiovascular disease with currently used medications. Importantly, scientists worked on developing tools to identify patients who are likely to develop ADRs. The development of genetic drug response prediction tools included discovery of novel biomarkers by next-generation sequencing in combination with statistical analysis to predict ADRs with a high specificity and sensitivity. New markers had to be validated in population-based data samples and clinical trials, followed by the steps leading to commercialization of the diagnostic tools. Exome sequencing was successfully completed in a large case control study for both ACEI angioedema and statin-induced myopathy. The data sets were analysed by TAXONOMY 3 interaction software and demonstrated the predictive power of 85 % and 84 % for myopathy and angioedema, respectively. Rare and common variants were found for both pharmacokinetic and immune genetic variants. In particular, they included a novel immune-modulatory gene family, the leukocyte immunoglobulin-like receptors (LILRs), in statin-induced and statin-independent muscle pain. Results for angioedema highlighted a role for potassium channels in side-effects of ACEI drugs, including the more common cough reaction. Therefore, the LILR Asp247 homozygous genotype is robustly associated with increased risk of ADRs associated with statin intolerance. While single testing at an individual drug start faces hurdles in terms of cost effectiveness, it is clear that preemptive whole-genome testing would be a major step to overcome this. PREDICTION-ADR initiated further study to implement and evaluate the impact of pharmacogenomics testing on therapy outcomes across several European clinical centres.
Keywords
Adverse drug reaction, pharmacogenetics, PREDICTION-ADR, statins, angiotensin converting enzyme inhibitors
