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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.

TitleQuantitative 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.
Publication TypeJournal Article
Year of Publication2007
AuthorsMuallem H, North KE, Kakoki M, Wojczynski MK, Li X, Grove M, Boerwinkle E, Wilhelmsen KC, Heiss G, Maeda N
JournalHum Genet
Volume121
Issue3-4
Pagination421-31
Date Published2007 May
ISSN0340-6717
Keywords3' Untranslated Regions, Animals, Atherosclerosis, Embryonic Stem Cells, European Continental Ancestry Group, Female, Gene Expression, Genes, Reporter, Haplotypes, Humans, Lipoproteins, Male, Mice, Polymorphism, Single Nucleotide, Receptors, LDL, Risk
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

DOI10.1007/s00439-007-0327-1
Alternate JournalHum Genet
PubMed ID17273844
Grant ListR37 HL042630 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
HL42630 / HL / NHLBI NIH HHS / United States