Analysis of polymorphisms in the 3' untranslated region of the LDL receptor gene and their effect on plasma cholesterol levels and drug response.
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.
Chen
Wei
W
VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Wang
Shukui
S
Ma
Yuling
Y
Zhou
Yue
Y
Liu
Haiyan
H
Strnad
Pavel
P
Kraemer
Fredric B
FB
Krauss
Ronald M
RM
Liu
Jingwen
J
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*
D020413:3' Untranslated Regions; D008055:Lipids; D011973:Receptors, LDL; D001599:Berberine; D002784:Cholesterol