Identification of Genetic Variants Associated With Response to Statin Therapy

Objective-The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins. Methods and Results-49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the epsilon 2, epsilon 3, and epsilon 4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (epsilon 2 carriers 53.8%, epsilon 3/epsilon 3 48.1%, and epsilon 4 carriers 46.4%, respectively, P=0.00039) and replicated in the pravastatin arm (epsilon 2 carriers 22.1%, epsilon 3/epsilon 3 21.8%, and epsilon 4 carriers 16.6%, respectively, P=0.00038). The proportion of subjects achieving an LDL-C <= 70 mg/dL at day 30 was higher for epsilon 2 than epsilon 4 carriers (P=1.3x10(-5)). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (GG 23.3%, non-G heterozygote 20.3%, and non-G homozygote 17.4%, P=0.042). Conclusion-Carriers of APOE epsilon 2 versus epsilon 4 had significantly greater LDL-C reduction with atorvastatin and with pravastatin, and more frequently achieved a guideline-recommended LDL-C <= 70 mg/dL. Polymorphisms in triallelic G2677T/A variant in ABCB1 were associated with the degree of LDL-C lowering with pravastatin. (Arterioscler Thromb Vasc Biol. 2009;29:1310-1315.)