Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels

BACKGROUND - High-density lipoprotein cholesterol (HDL) levels are a major risk factor for cardiovascular disease. Previously we identified a quantitative trait locus on baboon chromosome 18 that regulates HDL. From positional cloning studies and expression studies, we identified the endothelial lipase gene (LIPG) as the primary candidate gene for the quantitative trait locus. The mechanism by which LIPG variation influences HDL levels has not been determined. METHODS AND RESULTS - We identified 164 LIPG polymorphisms in a panel of sibling baboons discordant for HDL1 and genotyped putative regulatory polymorphisms in a population of 951 pedigreed baboons. With the use of quantitative trait nucleotide analysis we identified 3 polymorphisms in the LIPG promoter associated with variation in serum HDL1 levels. In addition, we demonstrated that these 3 polymorphisms affect LIPG promoter activity in vitro. In silico analysis was used to identify putative transcription factors that differentially bind the functional promoter polymorphisms. CONCLUSIONS - These results reveal LIPG variants that specifically contribute to HDL1 levels and demonstrate mechanisms by which these polymorphisms may regulate LIPG promoter activity. Results from the present study provide a mechanism, namely variation in LIPG promoter activity possibly caused by altered transcription factor binding, by which LIPG variation affects HDL levels.