title: Functional characterization of novel variants in the CETP promoter and the LIPC gene in subjects with hyperalphalipoproteinemia.
abstract: BACKGROUND
  Variants in the CETP and the LIPC genes, encoding cholesteryl ester transfer protein and hepatic lipase, respectively, are associated with high levels of HDL-cholesterol or hyperalphalipoproteinemia (HALP). Recently, we have identified three novel variants in the CETP promoter and two novel variants in LIPC in Thai subjects with HALP. In this study, we investigated the functions of these 5 variants in vitro.
  
  
  METHODS
  For CETP promoter variants, we used site-directed mutagenesis, transient expression in HepG2 cells and luciferase reporter assay. For LIPC variants, cDNA was cloned and mutagenesis for missense variants was performed before expression in HepG2 cells.
  
  
  RESULTS
  The transcriptional activities of -49G>T,-70C>T, and -372C>T CETP promoter variants were markedly reduced (5%, 8% and 30%, respectively, compared to that of the wild-type, P<0.001). For LIPC variants, hepatic lipase activities in the lysates of cells transfected with c.421A>G (p.G141S) and c.517G>A (p.V173M) variants were 41% and 46%, respectively, compared to that of the wild-type (P<0.05).
  
  
  CONCLUSIONS
  The recently-identified variants in the CETP promoter and in the LIPC gene may contribute to HALP. Our result may have a diagnostic application in the genetic evaluation of subjects with high HDL-cholesterol levels.
authors.affiliation: Hormonal and Metabolic Disorders Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Patumwan, Bangkok 10330, Thailand.
authors.forename: Wanee
authors.initials: W
authors.lastname: Plengpanich
authors.forename: Siraprapa
authors.initials: S
authors.lastname: Tongkobpetch
authors.forename: Vorasuk
authors.initials: V
authors.lastname: Shotelersuk
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.forename: Weerapan
authors.initials: W
authors.lastname: Khovidhunkit
mesh_terms: D000368:Aged; D053480:Cholesterol Ester Transfer Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D013785:Thailand
chemical_list: D053480:Cholesterol Ester Transfer Proteins; C504173:LIPC protein, human; D008049:Lipase