Identification of Promoter Variants in Baboon Endothelial Lipase That Regulate High-Density Lipoprotein Cholesterol Levels

Abstract

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.

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

“…The significant traits tended to be for larger HDLs that are enriched in apoE (10). This QTL cluster confirms our previous study involving many of the same traits and animals and in which we reported promoter variants in LIPG, the structural locus for endothelial lipase on chromosome 18, to regulate HDLC levels (22).…”

“…Seventeen LOD scores .10 were flanked by human microsatellite markers D18S475, D18S72, and D18S1156 (41.8, 51.9, and 61.5 cM). The baboon microsatellite marker D18Spha1 (57.4 cM) is located within exon 9 of the structural locus for endothelial lipase (LIPG) (22).…”

Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

“…This suggests that the HDL-C peak near LIPG in GWASs is not due to a coding variant but rather due to some type of regulatory variant. Interestingly, studies in baboons have suggested that LIPG promoter variants are associated with variation in HDL-C levels (15). Ongoing studies in our lab are addressing the role of promoter variants in the human LIPG gene and their association with plasma HDL-C levels.…”

“…Overexpression of EL in mice decreases HDL-C levels (13), whereas the inhibition or deletion of EL in mice increases HDL-C levels (14). In baboons, HDL-C levels have also been associated with variation in LIPG expression (15).…”

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol

“…For instance, in this report, we found that a nonsynonymous coding polymorphism in Abca1 was responsible for the QTL from the CAST crosses on Chr 4 whereas a difference in expression of Abca1 was responsible for the QTL from the PERA crosses. In addition, Lipg is accepted as a known HDL gene, but the molecular basis of observed association and linkage with HDL vary from a nonsynonymous coding polymorphism in humans ( 49 ) to a difference in expression of the gene in mice and baboons ( 29,50 ).…”