Analysis of polymorphisms in the 3 ' untranslated region of the LDL receptor gene and their effect on plasma cholesterol levels and drug response

作者：Chen Wei; Wang Shukui; Ma Yuling; Zhou Yue; Liu Haiyan; Strnad Pavel; Kraemer Fredric B; Krauss Ronald M; Liu Jingwen^*

来源：International Journal of Molecular Medicine, 2008, 21(3): 345-353.

• LDL receptor
• 3 ' untranslated region
• single nucleotide polymorphism
• berberine
• mRNA stability
• genetic variants

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 (r(2)= 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.

• 出版日期2008-3
• 单位南京医科大学