Ten allelic apolipoprotein[a] 5' flanking fragments exhibit comparable promoter activities in HepG2 cells.

Abstract

Plasma levels of the atherogenic lipoprotein[a] represent a quantitative genetic trait that is primarily controlled by the polymorphic apolipoprotein[a] locus on chromosome 6q. The more than 1000-fold variation in lipoprotein[a] plasma levels is explained to a large extent by a remarkable size polymorphism of the apolipoprotein[a] gene which is translated into apolipoprotein[a] isoforms and by unidentified sequence variation in apo[a]. In a recent report, sequence variation in a 1.5 kb fragment from the 5' flanking region of the apolipoprotein[a] gene was associated with different promoter activities, which led to the suggestion that transcriptional control of the apolipoprotein[a] gene might contribute significantly to lipoprotein[a] plasma levels. We have used a reporter gene assay to compare the promoter activities of these 1.5 kb fragments which were cloned from ten well-characterized apolipoprotein[a] alleles. These ten allelic apolipoprotein[a] fragments revealed, despite the same sequence variation as previously reported, comparable and relatively weak promoter activities in HepG2 hepatocarcinoma cells. Promoter activity for the same fragment in non-liver cells and the identification of a liver cell-specific DNaseI hypersensitive site 3 kb upstream from the ATG start codon suggest that longer fragments must be used in order to analyze the transcriptional regulation of the apolipoprotein[a] gene.