Analysis of polymorphisms in the 3' untranslated region of the LDL receptor gene and their effect on plasma cholesterol levels and drug response.
Analysis of polymorphisms in the 3' untranslated region of the LDL receptor gene and their effect on plasma cholesterol levels and drug response.
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DOI：
10.3892/ijmm.21.3.345
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发表时间：
2008-03
影响因子：
5.4
通讯作者：
Wei Chen-;Shukui Wang;Yuling Ma;Yue Zhou;Haiyan Liu;P. Strnad;F. Kraemer;R. Krauss;Jingwen Liu
中科院分区：
文献类型：
--
作者：
Wei Chen-;Shukui Wang;Yuling Ma;Yue Zhou;Haiyan Liu;P. Strnad;F. Kraemer;R. Krauss;Jingwen Liu
低密度脂蛋白受体(LDLR)基因3‘非翻译区(3’UTR)的近端含有重要的调控序列，控制信使的稳定性，并介导降胆固醇药物黄连素(BBR)诱导的LDLR mRNA半衰期的增加。在这项研究中，我们研究了该区域内的单核苷酸多态(SNPs)是否导致冠心病(CHD)的易感性，以及它们是否影响对BBR治疗的反应。从103例正常血脂受试者和94例高脂血症冠心病患者的外周血中提取基因组DNA。用聚合酶链式反应扩增LDLR基因3‘端非编码区1.1kb的片段并测序。在该区域检测到6个SNPs。其中，SNP1和SNP6在两个研究组中的存在完全相关(R2=1)。CHD患者个体SNPs频率和基因分型与正常血脂个体无明显差异。等位基因变异与总胆固醇和低密度脂蛋白水平无关。为了研究3‘非编码区的遗传变异对BBR治疗的影响，将3个常见SNP单倍型的3’非编码区的2.5kb全长克隆到荧光素酶报告基因中，并将报告载体导入HepG2细胞。BBR处理后，携带不同单倍型LDLR 3‘非编码区的报告基因表达水平也有不同程度的提高。综上所述，这些发现表明，中国人群中常见的3‘UTRLDLR基因多态性不会导致CHD的易感性，也不会影响血脂水平或BBR的降胆固醇作用。
The proximal section of the 3' untranslated region (3'UTR) of LDL receptor (LDLR) mRNA contains important regulatory sequences that control the messenger stability and mediate the cholesterol-lowering drug berberine (BBR)-induced increase in LDLR mRNA half-life. In the present study, we examined whether single nucleotide polymorphisms (SNPs) within this region cause a predisposition to the development of coronary heart disease (CHD) and whether they affect the response to BBR treatment. Genomic DNAs were isolated from peripheral blood of a Chinese cohort of 103 normolipidemic subjects and 94 hyperlipidemic CHD patients. The 1.1-kb proximal fragment of LDLR mRNA 3'UTR was PCR-amplified and sequenced. Six SNPs were detected within this region. Among them, the presence of SNP1 and SNP6 in both study groups showed complete association (r2=1). The frequency of individual SNPs and genotypes did not differ between CHD patients and normolipidemic individuals. Allelic variations did not correlate with total and LDL-cholesterol levels. To examine the effects of genetic variations in 3'UTR on BBR treatment, entire 2.5-kb regions of 3'UTR from three common SNP haplotypes were cloned into a luciferase reporter and the reporter constructs were transfected into HepG2 cells. The expression of reporter genes carrying different haplotypes of LDLR 3'UTR was increased to a similar extent upon BBR treatment. Taken together, these findings suggest that the 3'UTR LDLR polymorphisms commonly found in the Chinese population do not cause a predisposition to the development of CHD, nor do they affect the plasma lipid levels or the cholesterol-lowering effect of BBR.