S. Kakko et al., R451Q MUTATION IN THE CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) GENE IS ASSOCIATED WITH HIGH PLASMA CETP ACTIVITY, Atherosclerosis, 136(2), 1998, pp. 233-240
Cholesteryl ester transfer protein (CETP), as a candidate gene for dys
lipoproteinemia and coronary heart disease, was studied in 105 men wit
h low plasma concentrations of high density lipoprotein cholesterol (H
DL-C) and established coronary heart disease as well as in 515 randoml
y selected men and women. A one-nucleotide substitution (G to A) in ex
on 15, which changes arginine (451) to glutamine in CETP protein, was
detected by PCR-SSCP and direct sequencing and screened in the populat
ion sample by a simple PCR-based restriction assay. In the random popu
lation sample the allele frequency of the R451Q mutation was 1.9%. Men
heterozygous for the R451Q mutation (n = 7) had 27% higher CETP activ
ity than age-, body mass index-, smoking-and alcohol consumption-match
ed controls with normal genotype (n = 21; P = 0.003). Women heterozygo
us for the R451Q mutation (n = 7) had 16% lower total cholesterol comp
ared to matched controls (n = 21; P = 0.07), but no such difference wa
s detected in men. In the random population sample the correlation bet
ween plasma total cholesterol level and CETP activity was 0.19 (P = 0.
044), both in men and women. When women with total cholesterol over 5.
2 mmol/l were excluded from analysis, heterozygotes (n = 4) had plasma
CETP activity of 113 nmol/h/ml plasma, whereas those of normal genoty
pe (n = 12) had 103 nmol/h/ml plasma, but this difference was not stat
istically significant. Women heterozygous for the R451Q mutation and c
onsuming less than 10 g alcohol a week had 23% lower HDL-C compared to
women with the normal genotype (P = 0.032). In conclusion, we describ
e a mutation in the CETP gene associated with high plasma CETP activit
y in men and with low total cholesterol in women. Further studies are
needed to evaluate the effect of mutation on the risk of coronary hear
t disease. (C) 1998 Elsevier Science Ireland Ltd.