title: Genetic variants affecting alternative splicing of human cholesteryl ester transfer protein.
abstract: Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport, with decreased CETP activity increasing HDL levels. Formation of an alternative splice form lacking exon 9 (Δ9-CETP) has been associated with two single nucleotide polymorphisms (SNPs) in high linkage disequilibrium with each other, namely rs9930761 T>C located in intron 8 in a putative splicing branch site and rs5883 C>T in a possible exonic splicing enhancer (ESE) site in exon 9. To assess the relative effect of rs9930761 and rs5883 on splicing, mini-gene constructs spanning CETP exons 8 to 10, carrying all four possible allele combinations, were transfected into HEK293 and HepG2 cells. The minor T allele of rs5883 enhanced splicing significantly in both cell lines whereas the minor C allele of rs9930761 did not. In combination, the two alleles did not yield greater splicing than the rs5883 T allele alone in HepG2 cells. These results indicate that the genetic effect on CETP splicing is largely attributable to rs5883. We also confirm that Δ9-CETP protein is expressed in the liver but fails to circulate in the blood.
authors.affiliation: Center for Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University Wexner Medical Center, 5184A Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA. Electronic address: suhy.2@osu.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Suhy
authors.affiliation: Center for Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University Wexner Medical Center, 5184A Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hartmann
authors.affiliation: Center for Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University Wexner Medical Center, 5184A Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Newman
authors.affiliation: Center for Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University Wexner Medical Center, 5184A Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Papp
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, School of Medicine, Departments of Neuroscience and Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, School of Medicine, Departments of Neuroscience and Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
authors.affiliation: Center for Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University Wexner Medical Center, 5184A Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005091:Exons; D014644:Genetic Variation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007438:Introns; D008099:Liver / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger
keywords: Alternative splicing; CETP levels in liver and plasma; Cholesteryl ester transfer protein; Coronary artery disease; Statin