title: Regulation of cholesteryl ester transfer protein expression by upstream polymorphisms: reduced expression associated with rs247616.
abstract: BACKGROUND
  Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport by exchanging cholesteryl esters for triglycerides between high-density lipoprotein and low-density lipoprotein particles, effectively decreasing high-density lipoprotein cholesterol levels. Variants within a large haplotype block upstream of CETP (rs247616, rs173539) have been shown to be significantly associated with reduced expression; however, the underlying mechanism has not been identified.
  
  
  METHODS
  We analyzed the linkage structure of our top candidate single-nucleotide polymorphism (SNP), rs247616, and assessed each SNP of the haplotype block for potential interactions with transcription factor binding sites. We then used a reporter gene assay to assess the effect of three SNPs (rs247616, rs173539, and rs1723150) on expression in vitro.
  
  
  RESULTS
  Several variants in the upstream haplotype, including rs247616, rs173539, and rs1723150, disrupt or generate transcription factor binding sites. In reporter gene assays, rs247616 and rs173539 were found to significantly affected expression in HepG2 cells, whereas rs17231506 had no effect. rs247616 decreased expression by 1.7-fold (P<0.0001), whereas rs173539 increased expression by 2.2-fold (P=0.0006).
  
  
  CONCLUSIONS
  SNPs rs247616 and rs173539 are in high linkage disequilibrium (R=0.96, D'=1.00) and have the potential to regulate CETP expression. Although opposing effects suggest that regulation of CETP expression could vary between tissues, the minor allele of rs247616 and SNPs in high linkage with it were found to be associated with reduced expression across all tissues.
authors.affiliation: Department of Pharmacology, Center for Pharmacogenomics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Suhy
authors.forename: Katherine
authors.initials: K
authors.lastname: Hartmann
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Papp
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D001665:Binding Sites; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008040:Genetic Linkage; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D008156:Luciferases