Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.
Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.
复制标题
DOI：
10.1161/circgenetics.108.795013
复制
发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Ginsburg GS
中科院分区：
文献类型：
--
作者：
Voora D;Shah SH;Reed CR;Zhai J;Crosslin DR;Messer C;Salisbury BA;Ginsburg GS
他汀类药物降低低密度脂蛋白胆固醇 (LDLc) 的效果存在个体差异，而且他汀类药物降低 LDLc 剂量依赖性的遗传关联性研究有限。 509 名高脂血症患者被随机分配阿托伐他汀 10 mg、辛伐他汀 20 mg 或普伐他汀 10 mg（低剂量期），随后分别服用 80 mg、80 mg 和 40 mg（高剂量期）。对他汀类药物、胆固醇和脂蛋白代谢中的 31 个基因进行了测序，并使用多变量调整一般线性回归测试了次要等位基因频率 >2% 的 489 个单核苷酸多态性与低剂量下 LDLc 百分比降低的关联。然后在高剂量他汀类药物中重复低剂量分析中的显着关联。在低剂量下，只有 1 个单核苷酸多态性符合我们的实验范围显着性水平，即 ABCA1 rs12003906。 26 名受试者携带 rs12003906 的次要等位基因，该等位基因与 LDLc 减少减弱相关（携带者与非携带者的 LDLc 减少分别为 -24.1±2.6% 与 -32.2±1.5%；P=0.0001）。此外，我们复制了与 APOE ε3 等位基因和 LDLc 降低的相关性。在高剂量下，ABCA1 rs12003906 次要等位基因和 APOE ε3 等位基因的携带者改善了其 LDLc 降低，但与非携带者相比，LDLc 降低继续减弱（-30.5±4.0% 对比 -42.0±2.4%；P=0.005）和（-38.5±1.9% 对比 -45.3±2.8%；P=0.005）。 P=0.009），分别。 ABCA1 和 APOE ε3 等位基因中的内含子单核苷酸多态性与他汀类药物降低 LDLc 的效果相关，并鉴定出可能对他汀类药物最大程度降低 LDLc 具有抵抗力的个体。
There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins. Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies >2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers −24.1±2.6% versus −32.2±1.5%; P=0.0001). In addition, we replicated the association with the APOE ε3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE ε3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (−30.5±4.0% versus −42.0±2.4%; P=0.005) and (−38.5±1.9% versus −45.3±2.8%; P=0.009), respectively. An intronic single nucleotide polymorphism in ABCA1 and the APOE ε3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins.