Genetic variability determines drug response
Lipid-lowering therapy in the form of statins constitutes the most common regimen for preventing cardiovascular disease. Although drug administration results in a reduction of cardiovascular events by 20–30 %, clinical response is highly variable. Accumulating evidence suggests that this variability is linked to genetic variation. To further delineate this observation, the EU-funded project 'A pharmacogenomic study of statins in the elderly at risk for cardiovascular disease' (PHASE) aimed to study individuals' responses following statin use based on their genetic make-up. The ultimate goal was to develop personalised cholesterol-lowering drug therapy. For this purpose, PHASE researchers performed a genome-wide scan of 5 224 participants of the 'Prospective study of pravastatin in the elderly at risk' (PROSPER) project, a multi-national, randomised, placebo-controlled trial. Genotyping was carried out for 557 192 genetic variants and 2.5 million single nucleotide polymorphisms (SNPs) were imputed within the whole genome. Meta-analysis of the results in conjunction with the ASCOT and CARDS trials revealed a role of the ApoE and the LPa genes in the pharmacogenetics of statins with respect to low-density lipoprotein (LDL) lowering. In collaboration with the WOSCOPS and CARE trials, the PHASE study found independently that genetic variation within the DNAJC5B gene influences the risk of a myocardial infarction after statin use. Collaboration with other genome-wide association studies is expected to portray the pharmacogenetic interactions of statin use and genomic variation on other clinical outcomes. In particular, the CHARGE consortium, in collaboration with the GIST consortium, will extend the PHASE study population, thereby increasing the statistical significance of its results. Collectively, the PHASE project helped reveal some important pharmacogenetic interactions of statin use and genetic variation on either LDL lowering or myocardial infarction following statin treatment. Such information will lead to improvements in the use of personalised therapy based on an individual's genetic profile.