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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1310.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

Identification of Genetic Variants Associated With Response to Statin Therapy

Jessica L. Mega; David A. Morrow; Alison Brown; Christopher P. Cannon; Marc S. Sabatine

From the TIMI Study Group, Cardiovascular Division, Department of Medicine (J.L.M., D.A.M., C.P.C., M.S.S.), Brigham & Women’s Hospital, and Harvard Medical School; and the Harvard Medical School-Partners Center for Personalized Genetic Medicine (A.B.), Boston, Mass.

Correspondence to Jessica L. Mega, MD, MPH, Brigham and Women’s Hospital, 350 Longwood Avenue, 1st Floor, Boston, MA 02115. E-mail jmega{at}partners.org

Abstract

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 2, 3, and 4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (2 carriers 53.8%, 3/3 48.1%, and 4 carriers 46.4%, respectively, P=0.00039) and replicated in the pravastatin arm (2 carriers 22.1%, 3/3 21.8%, and 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 2 than 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 2 versus 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.

In this study involving statin-treated subjects and polymorphisms in 9 genes, carriers of the APOE 2 haplotype versus 4 haplotype had significantly lower baseline LDL-C, greater LDL-C reduction with atorvastatin and pravastatin, and more frequently achieved a guideline-recommended LDL-C 70 mg/dL. A variant in ABCB1 was associated with the degree of LDL lowering with pravastatin.

Key Words: cholesterol-lowering drugs • lipids • pharmacogenetics