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

Laura A. Cox, Shifra Birnbaum, Michael C. Mahaney, David L. Rainwater, Jeff T. Williams, John L. VandeBerg

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1185-1195
Number of pages11
JournalCirculation
Volume116
Issue number10
DOIs
StatePublished - Sep 2007
Externally publishedYes

Fingerprint

Papio
Lipase
HDL Cholesterol
Genes
Quantitative Trait Loci
Transcription Factors
Chromosomes, Human, Pair 18
Computer Simulation
Organism Cloning
Cardiovascular Diseases
Nucleotides

Keywords

  • Cardiovascular diseases
  • Cholesterol
  • Gene expression
  • Genetic polymorphisms
  • Genetics
  • Genomics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cox, L. A., Birnbaum, S., Mahaney, M. C., Rainwater, D. L., Williams, J. T., & VandeBerg, J. L. (2007). Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels. Circulation, 116(10), 1185-1195. https://doi.org/10.1161/CIRCULATIONAHA.107.704346

Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels. / Cox, Laura A.; Birnbaum, Shifra; Mahaney, Michael C.; Rainwater, David L.; Williams, Jeff T.; VandeBerg, John L.

In: Circulation, Vol. 116, No. 10, 09.2007, p. 1185-1195.

Research output: Contribution to journalArticle

Cox, LA, Birnbaum, S, Mahaney, MC, Rainwater, DL, Williams, JT & VandeBerg, JL 2007, 'Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels', Circulation, vol. 116, no. 10, pp. 1185-1195. https://doi.org/10.1161/CIRCULATIONAHA.107.704346
Cox, Laura A. ; Birnbaum, Shifra ; Mahaney, Michael C. ; Rainwater, David L. ; Williams, Jeff T. ; VandeBerg, John L. / Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels. In: Circulation. 2007 ; Vol. 116, No. 10. pp. 1185-1195.
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AB - 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.

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