10 ALLELIC APOLIPOPROTEIN[A] 5' FLANKING FRAGMENTS EXHIBIT COMPARABLEPROMOTER ACTIVITIES IN HEPG2 CELLS

Plasma levels of the atherogenic lipoprotein[a] represent a quantitati ve genetic trait that is primarily controlled by the polymorphic apoli poprotein[a] locus on chromosome 6q. The more than 1000-fold variation in lipoprotein[a] plasma levels is explained to a large extent by a r emarkable size polymorphism of the apolipoprotein[a] gene which is tra nslated into apolipoprotein[a] isoforms and by unidentified sequence v ariation 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 wa s associated with different promoter activities, which led to the sugg estion that transcriptional control of the apolipoprotein[a] gene migh t contribute significantly to lipoprotein[a] plasma levels. We have us ed a reporter gene assay to compare the promoter activities of these 1 ,5 kb fragments which were cloned from ten well-characterized apolipop rotein[a] alleles. These ten allelic apolipoprotein[a] fragments revea led, despite the same sequence variation as previously reported, compa rable and relatively weak promoter activities in HepG2 hepatocarcinoma cells. Promoter activity for the same fragment in nonliver 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.