Mega Jessica L, Morrow David A, Brown Alison, Cannon Christopher P, Sabatine Marc S
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1310-5. doi: 10.1161/ATVBAHA.109.188474. Epub 2009 Aug 10.
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.
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).
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.
本研究旨在测试参与低密度脂蛋白胆固醇（LDL-C）代谢或他汀类药物药代动力学的基因多态性与他汀类药物降低LDL-C之间的关联。
对1507例急性冠状动脉综合征（ACS）后随机接受阿托伐他汀或普伐他汀治疗的受试者进行了9个基因中49个标签和候选多态性的基因分型。定义载脂蛋白E的ε2、ε3和ε4异构体的两个多态性（rs7412、rs429358）与阿托伐他汀降低LDL-C的百分比显著相关（ε2携带者分别为53.8%，ε3/ε3为48.1%，ε4携带者为46.4%，P=0.00039），并在普伐他汀组中得到重复验证（ε2携带者分别为22.1%，ε3/ε3为21.8%，ε4携带者为16.6%，P=0.00038）。在第30天时，ε2携带者达到LDL-C≤70mg/dL的受试者比例高于ε4携带者（P=1.3×10⁻⁵）。在普伐他汀组中，ABCB1基因的三等位基因rs2032582变体（G2677T/A）与LDL-C降低的百分比相关（GG为23.3%，非G杂合子为20.3%，非G纯合子为17.4%，P=0.042）。
与ε4相比，APOE ε2携带者使用阿托伐他汀和普伐他汀时LDL-C降低更为显著，且更频繁地达到指南推荐的LDL-C≤70mg/dL。ABCB1基因三等位基因G2677T/A变体的多态性与普伐他汀降低LDL-C的程度相关。
