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.


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 epsilon2, epsilon3, and epsilon4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (epsilon2 carriers 53.8%, epsilon3/epsilon3 48.1%, and epsilon4 carriers 46.4%, respectively, P=0.00039) and replicated in the pravastatin arm (epsilon2 carriers 22.1%, epsilon3/epsilon3 21.8%, and epsilon4 carriers 16.6%, respectively, P=0.00038). The proportion of subjects achieving an LDL-C < or =70 mg/dL at day 30 was higher for epsilon2 than epsilon4 carriers (P=1.3 x 10(-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).


CONCLUSIONS
Carriers of APOE epsilon2 versus epsilon4 had significantly greater LDL-C reduction with atorvastatin and with pravastatin, and more frequently achieved a guideline-recommended LDL-C < or =70 mg/dL. Polymorphisms in triallelic G2677T/A variant in ABCB1 were associated with the degree of LDL-C lowering with pravastatin.
Mega
Jessica L
JL
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. jmega@partners.org
Morrow
David A
DA
Brown
Alison
A
Cannon
Christopher P
CP
Sabatine
Marc S
MS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D000069059:Atorvastatin; D001711:Biotransformation / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood; D006239:Haplotypes; D006538:Heptanoic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D017410:Practice Guidelines as Topic; D017035:Pravastatin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D017035:Pravastatin