GeneticsLandmark
Large Copenhagen study shows CETP-mutation-driven HDL elevation actually raises heart disease risk in women, not lowers it (Circulation 2000)
Original title: Elevated HDL cholesterol is a risk factor for ischemic heart disease in white women when caused by a common mutation in the cholesteryl ester transfer protein gene
Since HDL-cholesterol is inversely related to ischemic heart disease (IHD) risk, this study tested whether the CETP Ile405Val mutation, which affects HDL-cholesterol levels, also affects IHD risk, in 9168 women and men from the general population and 946 women and men with IHD, all white. Genotype frequencies were 0.46 Ile/Ile, 0.43 Ile/Val, and 0.11 Val/Val in both sexes. Women with these genotypes had mean HDL-cholesterol of 1.68, 1.75, and 1.82 mmol/L respectively (P less than 0.001), with a corresponding decrease in the total-to-HDL-cholesterol ratio (P=0.002). In multiple logistic regression, women not on hormone replacement therapy who were Val405 heterozygous or homozygous had a 1.4-fold to 2.1-fold increased IHD risk; no significant associations were found in men. The authors conclude that HDL-cholesterol elevation caused by this CETP mutation is associated with increased, not decreased, IHD risk in white women.
Original abstract
Background: The level of HDL cholesterol is inversely related to the risk of ischemic heart disease.
Methods And Results: In 9168 women and men from a general population and 946 women and men with ischemic heart disease (all white), we tested the hypothesis that the Ile405Val mutation in the cholesteryl ester transfer protein gene (CETP) affects HDL cholesterol levels and the risk of ischemic heart disease. The relative frequencies of Ile/Ile, Ile/Val, and Val/Val carriers were 0.46, 0.43, and 0.11 for both women and men. Women with these 3 genotypes had mean HDL cholesterol levels of 1.68, 1.75, and 1.82 mmol/L, respectively (P<0.001, ANOVA), as well as a significant decrease in the ratio of total to HDL cholesterol (P=0. 002, ANOVA). On multiple logistic regression analysis, women not treated with hormone replacement therapy who were heterozygous or homozygous for Val405 had a 1.4-fold (95% CI 1.0 to 1.9) to 2.1-fold (95% CI 1.3 to 3.4) increase in the risk of ischemic heart disease. No significant associations were found in men.
Conclusions: Increased HDL cholesterol levels caused by mutations in CETP are associated with an increased risk of ischemic heart disease in white women.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.