Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.
Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.
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DOI：
10.1161/atvbaha.110.203273
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Krauss RM
中科院分区：
文献类型：
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作者：
Mangravite LM;Medina MW;Cui J;Pressman S;Smith JD;Rieder MJ;Guo X;Nickerson DA;Rotter JI;Krauss RM
尽管他汀类药物对降低低密度脂蛋白胆固醇（LDL-cholesterol， LDLC）有效，但个体间的反应差异很大。我们测试了LDLR和HMGCR共同等位基因的联合作用对这种变异性的影响程度。在胆固醇和药物遗传学（CAP）试验（335名非洲裔美国人和609名欧洲裔美国人）中，检测了LDLR 3 ' -非翻译区（3UTR）的单倍型与辛伐他汀治疗降脂反应的关系。在非裔美国人中，LDLR单倍型5 （L5）与辛伐他汀诱导的ldl、总胆固醇、非高密度脂蛋白胆固醇和载脂蛋白B的较小降低相关（P= 0.0002-0.03），但与欧裔美国人无关。与非携带者（- 30.6±1.5% N=78， P=0.0001）和任一个体单倍型携带者（- 28.2±1.1% N=158， P=0.001）相比，L5和先前描述的HMGCR单倍型在非洲裔美国人中联合存在与载脂蛋白ob减少显著相关（- 22.4±1.5% N=89）。在使用淋巴母细胞系测量辛伐他汀介导的LDLR表面表达诱导时，我们观察到类似的差异（P=0.03）。我们已经确定了一种常见的LDLR 3UTR单倍型，它与辛伐他汀治疗的降脂反应减弱有关。LDLR和先前描述的HMGCR单倍型个体的反应进一步降低。先前发现的他汀类药物疗效的种族差异部分可以通过这些组合单倍型在非裔美国人中增加的患病率来解释。
Although statins are efficacious for lowering LDL-cholesterol (LDLC), there is wide inter-individual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability. Haplotypes in the LDLR 3′-untranslated region (3UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics (CAP) trial (335 African-Americans and 609European-Americans). LDLR haplotype 5 (L5)was associated with smaller simvastatin-induced reductions in LDLC, total cholesterol, non-HDL cholesterol, and apolipoprotein B (P=0.0002–0.03)in African-Americans, but not European-Americans. The combined presence of L5 and previously described HMGCR haplotypes in African-Americans was associated with significantly attenuated apoB reduction(−22.4±1.5% N=89) both compared to noncarriers (−30.6±1.5% N=78, P=0.0001) and to carriers of either individual haplotype (−28.2±1.1% N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of LDLR surface expression using lymphoblast cell lines (P=0.03). We have identified a common LDLR 3UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by increased prevalence of these combined haplotypes in African-Americans.