Cholesteryl ester transfer protein promoter single-nucleotide polymorphisms in Sp1-binding sites affect transcription and are associated with high-density lipoprotein cholesterol.
Genetic variation in the human cholesteryl ester transfer protein (CETP) promoter has been shown to be associated with high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease. Some of this variation occurs in Sp1/Sp3 binding sites in the proximal promoter. We find that both the known promoter polymorphism at -629 and the previously uncharacterized polymorphism at -38 are associated with HDL-C levels in vivo and affect transcription in vitro. While the -629 polymorphism is common in all ethnic groups, the -38 polymorphism is found at significant levels (6.4%) only among African Americans. Those homozygous for the less common -38A allele have higher HDL-C levels than those with the more frequent -38G allele. This association was found in a population of African Americans at risk of cardiovascular disease and then replicated in a different population chosen from among patients with extremes of HDL-C. When studied in vitro, the most transcriptionally active allele (-629C/-38G) yields 51% more reporter protein than the least active allele (-629A/-38A) in HepG2 cells. These transcriptional effects reflect the projected impact of increased CETP expression on HDL-C phenotypes seen in vivo.
Genomic and Proteomic Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, CT, USA. john_f_thompson@groton.pfizer.com
J F
JF
Thompson
D B
DB
Lloyd
M E
ME
Lira
P M
PM
Milos
D001741:Black or African American; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D017931:DNA Primers; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008156:Luciferases; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D017931:DNA Primers; D006023:Glycoproteins; D016329:Sp1 Transcription Factor; D008156:Luciferases