title: Analysis of polymorphisms in the 3' untranslated region of the LDL receptor gene and their effect on plasma cholesterol levels and drug response.
abstract: 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.
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Shukui
authors.initials: S
authors.lastname: Wang
authors.forename: Yuling
authors.initials: Y
authors.lastname: Ma
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.forename: Fredric B
authors.initials: FB
authors.lastname: Kraemer
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002681:China; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020871:RNA Stability; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D008055:Lipids; D011973:Receptors, LDL; D001599:Berberine; D002784:Cholesterol