University of Oulu

Role of polymorphisms of the cholesteryl ester transfer protein gene in atherogenesis

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Author: Kakko, Sakari1
Organizations: 1University of Oulu, Faculty of Medicine, Department of Internal Medicine
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 8.8 MB)
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Language: English
Published: 2000
Publish Date: 2000-03-28
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 10 of the University Hospital of Oulu, on May 31st, 2000, at 2 p.m.
Reviewer: Professor Christian Ehnholm
Professor Timo Kuusi


The cholesteryl ester transfer protein (CETP) is a plasma protein that transfers cholesteryl esters and triglycerides between plasma lipoproteins. Humans with a genetic CETP deficiency have high plasma high density lipopoprotein cholesterol (HDL-C) levels, whereas the CETP transgene lowers plasma HDL-C levels in mice. The role of CETP in the development of atherosclerosis is unclear due to the controversial results of many human and animal studies. The present research was designed to investigate the CETP gene as a candidate gene in the regulation of plasma HDL-C levels and the development of atherosclerosis in humans. The CETP gene was screened for mutations and polymorphisms associated with these traits in a well-characterized, homogenous population sample of 515 men and women and in a sample of 115 men with low HDL-C levels and coronary heart disease (CHD).

Using polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP), three polymorphic sites were found (A373P, I405V, R451Q) in the exons of the CETP gene, one in intron 9 and one in the 3'untranslated region of the CETP gene. In addition, the genotypes of a functional promoter polymorphism were determined.

The V405 allele was associated with lower plasma CETP activity in the whole population sample, and the Q451 allele and the P373 allele were associated with higher plasma CETP activity in men, whereas the genotypes of the promoter polymorphism were not significantly associated with plasma CETP activity. The genotypes of the CETP gene explained about 20 % of the variation of plasma CETP activity in men. The CETP gene polymorphisms were found to be a minor regulator of plasma HDL-C levels, and these associations interacted with alcohol consumption, sex and triglyceride levels. The strongest association was detected between the promoter polymorphism and HDL-C levels in women. The variation at the CETP gene locus explained about 8 % of the variation in plasma HDL-C levels in women, but less than 1 % in men. CETP gene polymorphisms (A373P, I405V and R451Q) were associated with carotid intima-media thickness, explaining about 6 % of the variation in men and 4 % in women. However, none of the polymorphisms were associated significantly with the CHD risk.

In conclusion, the CETP gene was found to be polymorphic and a minor regulator of plasma HDL-C levels and the development of atherosclerosis.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-5578-X
ISBN Print: 951-42-5577-1
Issue: 580
Copyright information: © University of Oulu, 2000. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.