No genetic determinants of differential cardiovascular event reduction by pravastatin in the PROSPER/PHASE study
Iris Postmus, Stella Trompet, Anton J. M. de Craen, Dov Shiffman, James J. Devlin, Ian Ford, Naveed A. Sattar, David J. Stott, P. Eline Slagboom, J. Wouter Jukema, on behalf of PROSPER/PHASE study · European Heart Journal · 2013
Purpose: Statin therapy is widely used in the prevention and treatment of cardiovascular events and is in general 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 variable drug response. Therefore we investigated the interaction between genetic variation and the effect of pravastatin therapy on the incidence of cardiovascular events. Methods: A genome-wide association study was performed in the participants of the PROSPER/PHASE study (n=5244). We used a logistic regression model with an interaction term between pravastatin treatment and genetic variation adjusted for sex and age, and country to correct for the within-study population structure. SNPs with p-values < 1x10-4 were replicated in two pravastatin trials, CARE (n=711) and WOSCOPS (n=522). Results: We did not find genome-wide significant (p<5x10-8) associations with differential cardiovascular event reduction by pravastatin therapy. Loci with low p-values (p<1x10-5) were observed within ADAMTS14 (chr 10) and PPP2R5E (chr 14), and near ODZ4 (chr 11), XKR4 (chr 8), METTL4 (chr 18), and TMEM215 (chr 9). None of the SNPs were replicated significantly in the CARE and WOSCOPS studies. Conclusion: Although our study was sufficiently powered to detect genetic interactions, we could not identify any genome-wide significant signal associated with differential event reduction by pravastatin treatment in a large prospective study. Since we were not able to detect any association within 5200 participants, we expect that relevant use of pharmacogenetics of statin therapy in clinical care will be limited. We assume that exploring biological mechanisms of statin therapy is a more realistic goal in genetics than developing personalized pravastatin therapy.