title: Point mutation (-69 G-->A) in the promoter region of cholesteryl ester transfer protein gene in Japanese hyperalphalipoproteinemic subjects.
abstract: Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo) B-containing lipoproteins and plays a crucial role in reverse cholesterol transport, which is a major protective system against atherosclerosis. Genetic CETP deficiency is the most common cause of a marked hyperalphalipoproteinemia (HALP) in the Japanese, and various mutations have been identified in the coding region as well as in the exon/intron boundaries in the CETP gene. In the present study, we identified a novel mutation in the promoter region of the CETP gene. This mutation was a G-to-A substitution at the -69 nucleotide of the promoter region (-69 G-->A), corresponding to the second nucleotide of the PEA3/ETS binding site (CGGAA) located upstream of the putative TATA box. Four (2.0%) of 196 unrelated subjects with a marked HALP (HDL cholesterol >/=2.59 mmol/L=100 mg/dL) were revealed to be heterozygous for the -69 G-->A mutation, and the allelic frequency of the mutant was 0.0102 in the subjects with a marked HALP. The subjects with the -69 G-->A mutation had low plasma CETP levels. Reporter gene assay showed that this mutation markedly reduced the transcriptional activities in HepG2 cells (8% of wild type). These results suggested that this mutation would be dominant negative. In conclusion, a novel -69 G-->A mutation in the CETP gene causes the decreased transcriptional activity leading to HALP.
authors.affiliation: Research Department, R&D Center, BML, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nagano
authors.forename: S
authors.initials: S
authors.lastname: Yamashita
authors.forename: K
authors.initials: K
authors.lastname: Hirano
authors.forename: T
authors.initials: T
authors.lastname: Kujiraoka
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Sagehashi
authors.forename: H
authors.initials: H
authors.lastname: Hattori
authors.forename: N
authors.initials: N
authors.lastname: Nakajima
authors.forename: T
authors.initials: T
authors.lastname: Maruyama
authors.forename: N
authors.initials: N
authors.lastname: Sakai
authors.forename: T
authors.initials: T
authors.lastname: Egashira
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins; D005260:Female; D005787:Gene Frequency; D006023:Glycoproteins; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood / Q000235:genetics*; D007564:Japan; D008055:Lipids / Q000097:blood; D008297:Male; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008055:Lipids; D014157:Transcription Factors; C065788:transcription factor PEA3