Role of polymorphisms of the cholesteryl ester transfer protein gene in atherogenesis
Abstract 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...
| Main Author: | |
|---|---|
| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
University of Oulu
2000
|
| Subjects: | |
| Online Access: | http://urn.fi/urn:isbn:951425578X http://nbn-resolving.de/urn:isbn:951425578X |
| Summary: | Abstract
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.
|
|---|