Abstract 1135: Statin Pharmacogenetics: Identification of Genetic Variants that Predict Response to Atorvastatin and Pravastatin
Background: LDL cholesterol (LDL-C) reduction in response to statins varies widely, with many patients not reaching target goals. We hypothesized that polymorphisms in LDL-C metabolism and statin pharmacokinetic genes would be associated with magnitude of LDL-C reduction with statin therapy.
Methods: 49 tagging and candidate polymorphisms were selected in 9 genes and their associations with statin efficacy were tested in 1507 post-ACS subjects randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d.
Results: Two variants in APOE (rs7412 and rs429358) were significantly associated with baseline LDL-C (P=7.9×10 −9 and P=0.0032) and determine the isoforms ϵ2, ϵ3, and ϵ4 of apolipoprotein E. After adjustment for baseline LDL-C and clinical features, the percent reduction in LDL-C from baseline to day 30 was greatest in ϵ2 carriers, intermediate in ϵ3/ϵ3 individuals, and least in ϵ4 carriers with atorvastatin (Ptrend=0.00039) and pravastatin (Ptrend=0.00038), (Fig⇓, Top). The percent of subjects achieving an LDL-C of ≤70 mg/dl was higher for ϵ2 carriers than ϵ4 carriers (atorvastatin Ptrend=0.00037 and pravastatin Ptrend=0.0084) (Fig⇓, Bottom). The HR for CV death, MI, or stroke over 2 yrs for ϵ2 carriers vs ϵ3/ϵ3 individuals was 0.78 (95% CI 0.40 – 1.51).
Conclusion: Evaluating genetic variants in 9 genes, we found that carriers of APOE ϵ2 versus ϵ4 had significantly lower baseline LDL-C, greater LDL-C reduction with atorvastatin or pravastatin, and more frequently achieved a goal of LDL-C ≤70 mg/dl. These findings add to the understanding of the genetic mechanisms that influence statin efficacy and suggest that common variants, such as the ones in APOE, may help tailor treatments.