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 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.