R451Q mutation in the cholesteryl ester transfer protein (CETP) gene is associated with high plasma CETP activity.

Cholesteryl ester transfer protein (CETP), as a candidate gene for dyslipoproteinemia and coronary heart disease, was studied in 105 men with low plasma concentrations of high density lipoprotein cholesterol (HDL-C) and established coronary heart disease as well as in 515 randomly selected men and women. A one-nucleotide substitution (G to A) in exon 15, which changes arginine (451) to glutamine in CETP protein, was detected by PCR-SSCP and direct sequencing and screened in the population sample by a simple PCR-based restriction assay. In the random population sample the allele frequency of the R451Q mutation was 1.9%. Men heterozygous for the R451Q mutation (n = 7) had 27% higher CETP activity than age-, body mass index-, smoking- and alcohol consumption-matched controls with normal genotype (n = 21; P = 0.003). Women heterozygous for the R451Q mutation (n = 7) had 16% lower total cholesterol compared to matched controls (n = 21; P = 0.07), but no such difference was detected in men. In the random population sample the correlation between 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 genotype (n = 12) had 103 nmol/h/ml plasma, but this difference was not statistically significant. Women heterozygous for the R451Q mutation and consuming 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 describe a mutation in the CETP gene associated with high plasma CETP activity in men and with low total cholesterol in women. Further studies are needed to evaluate the effect of mutation on the risk of coronary heart disease.