A promoter polymorphism in cholesterol 7α-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin
A promoter polymorphism in cholesterol 7α-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin
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DOI：
10.1016/j.atherosclerosis.2004.12.019
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发表时间：
2005-06-01
期刊：
影响因子：
5.3
通讯作者：
Schaefer, EJ
中科院分区：
文献类型：
--
作者：
Kajinami, K;Brousseau, ME;Schaefer, EJ
胆汁酸生物合成是细胞内胆固醇的关键决定因素，进而是肝细胞中胆固醇合成速率的关键决定因素。这表明胆固醇7 α-羟化酶基因（CYP 7A 1）（胆汁酸生物合成的关键酶）的变异可能影响他汀类药物的反应。为了验证这一假设，在324例接受阿托伐他汀10 mg治疗的高胆固醇血症患者中检查了CYP 7A 1的启动子多态性（A-204 C）。变异C等位基因与低密度脂蛋白胆固醇降低不佳显著且独立相关;野生型等位基因纯合子为-39%，变异等位基因杂合子为-37%，变异等位基因纯合子为-34%（趋势p < 0.0001）。在男性中，差异更为显著，并且由于载脂蛋白E基因（APOE）的常见变体（APOE 2或APOE 4）的共存而增强。在两个基因座都具有野生型等位基因的受试者中，LDL胆固醇的平均降低为-40%，而在具有两个CYP 7A 1变体等位基因和至少一个变体APOE等位基因的受试者中，该值为-31%（p < 0.0001）。这两个位点的组合分析比两个单位点分析更准确地预测目标LDL胆固醇的实现。我们得出结论，CYP 7A 1 A-204 C启动子变体与对阿托伐他汀的不良反应相关，其被另一个基因座APOE中的常见变体相加增强。(c)2004爱思唯尔爱尔兰有限公司保留所有权利。
Bile-acid biosynthesis is a key determinant of intracellular cholesterol and, in turn, cholesterol synthesis rate in hepatocytes. This suggests that variation in the cholesterol 7 alpha-hydroxylase gene (CYP7A1), a key enzyme in bile-acid biosynthesis, may influence the statin response. To test this hypothesis, a promoter polymorphism (A-204C) in CYP7A1 was examined in 324 hypercholesterolemic patients treated with atorvastatin 10 mg. The variant C allele was significantly and independently associated with poor LDL cholesterol reductions; -39% in wild type allele homozygotes, -37% in variant allele heterozygotes, and -34% in variant allele homozygotes (p < 0.0001 for trend). Differences were more striking in men, and were enhanced by the coexistence of common variants of apolipoprotein E gene (APOE), epsilon 2 or epsilon 4. In subjects having wild type alleles at both loci, the mean reduction in LDL cholesterol was -40%, while the value in subjects having two CYP7A1 variant alleles and at least one variant APOE allele was -31% (p < 0.0001). Combination analysis of these two loci more accurately predicted the achievement of goal LDL cholesterol, than did both single locus analysis. We concluded that the CYP7A1 A-204C promoter variant was associated with poor response to atorvastatin, which were additively enhanced by common variants in another locus, APOE. (c) 2004 Elsevier Ireland Ltd. All rights reserved.