title: Quantitative effects of common genetic variations in the 3'UTR of the human LDL-receptor gene and their associations with plasma lipid levels in the Atherosclerosis Risk in Communities study.
abstract: The low-density lipoprotein receptor (LDLR) plays a pivotal role in cholesterol homeostasis. However, the role of genetic variations in the 3'UTR of the LDLR in relation to plasma cholesterol has been largely understudied. Six SNPs, G44243A, G44332A, C44506G, G44695A, C44857T and A44964G, within the 5' region of the 3'UTR fall into three common haplotypes, GGCGCA, AGCACG, and GGCGTA, occurring at frequencies of 0.45, 0.31 and 0.17, respectively, in Caucasians (n = 29) and 0.13, 0.13 and 0.38, respectively, in African Americans (n = 32), with three other haplotypes occurring at lesser frequencies. In a tissue culture based system, expression of a reporter gene carrying a 3'UTR that includes the 1 kb nucleotide sequences corresponding to the AGCACG or GGCGTA was 70 or 63%, respectively, of the same sequence with GGCGCA. Genotyping of two "haplotype tagging" SNPs, C44857T and A44964G, in the Atherosclerosis Risk in Communities (ARIC) study population showed that in Caucasians, but not in African Americans, the inferred TA haplotype had a significant LDL-cholesterol lowering effect. The adjusted LDL-cholesterol levels in the TA/TA diplotypes were lower by 6.10 mg/dl in men (P < 0.001) and by 4.63 mg/dl in women (P < 0.01) than in individuals with other diplotypes. Caucasian men homozygous for CA, in contrast, showed significantly higher LDL-cholesterol (P < 0.04), lower HDL-cholesterol (P < 0.02) and higher LDL/HDL ratios (P < 0.001). Thus our data shows that 3'UTR sequences that cause higher reporter gene expression in vitro are associated in Caucasians with plasma lipid profiles indicative of higher cardiovascular risk, suggesting that further studies of quantitative variants in the LDLR gene will be valuable.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
authors.forename: Hind
authors.initials: H
authors.lastname: Muallem
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
authors.forename: Mary K
authors.initials: MK
authors.lastname: Wojczynski
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Megan
authors.initials: M
authors.lastname: Grove
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Wilhelmsen
authors.forename: Gerardo
authors.initials: G
authors.lastname: Heiss
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D053595:Embryonic Stem Cells; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D006239:Haplotypes; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*; D012306:Risk; D044465:White People / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D008074:Lipoproteins; D011973:Receptors, LDL