In search for genetic determinants of clinically meaningful differential cardiovascular event reduction by pravastatin in the PHArmacogenetic study of Statins in the Elderly at risk (PHASE)/PROSPER study

Background: Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response. Methods and results: We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease-PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n=5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1×10^-4 were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n=711) and WOSCOPS (n=522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p=0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing. Conclusions: We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited.