Genetics
A bimodal CETP concentration pattern hints at hidden CETP mutations linked to I405V, raising heart disease risk in men with high triglycerides (J Lipid Res 1998)
Original title: Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia
Since high triglycerides and low HDL-cholesterol together raise coronary heart disease (CHD) risk, this study examined the CETP I405V polymorphism in relation to CETP and HDL levels and CHD prevalence in 576 men of Japanese ancestry from the Honolulu Heart Program. Plasma CETP concentration differed by genotype (1.95, 1.91, 1.77 microgram/mL for II, IV, VV), with a bimodal distribution seen only among VV men (P less than 0.01), suggesting a functionally significant mutation in a subset of V alleles. HDL-cholesterol was higher in VV than IV or II men (55.4, 51.3, 51.1 mg/dL, P less than 0.04), significant only in VV men with triglycerides above 165 mg/dL. Overall CHD prevalence did not differ by genotype, but among high-triglyceride men, CHD prevalence appeared higher in VV than IV or II (38% vs 27% vs 18%, P less than 0.05 for interaction).
Original abstract
Plasma triglyceride (TG) levels are inversely related to HDL-cholesterol levels and subjects with high TG and low HDL cholesterol have increased coronary heart disease (CHD) risk. Plasma cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to TG-rich lipoproteins. In this study we determined the relationship between a common CETP amino acid polymorphism (I405V) and CETP and HDL levels and CHD prevalence in 576 men of Japanese ancestry in the Honolulu Heart Program cohort. This conservative substitution was associated with altered plasma CETP concentration (1.95 +/- 0.54, 1.91 +/- 0.57, and 1.77 +/- 0.57 microg/ml for the II, IV and VV genotypes, respectively). The distribution of plasma CETP concentrations among the VV, but not II, men appeared bimodal (P < 0.01), suggesting the presence of a functionally significant CETP gene mutation(s) in a subset of V alleles. HDL-C levels were higher in VV than IV for II men (55.4 +/- 17.4, 51.3 +/- 16.6, 51.1 +/- 17.0 mg/dl, P < 0.04). However, the increase in HDL was only significant in VV men with plasma TG > 165 mg/dl. Although CHD prevalence was not significantly different among the three genotypes in this population, in the subpopulation with high plasma TG, CHD prevalence appeared higher among VV than IV or II subjects (38% vs. 27% vs. 18%, P < 0.05 for an interaction of genotype and plasma TG levels). In fresh plasma from a separate group of normolipidemic subjects, the V/I polymorphism was not associated with any change in plasma CETP specific activity. The data suggest that a widespread and common CETP gene mutation(s) in linkage disequilibrium with 405V causes low CETP. Among hypertriglyceridemic men this is associated with higher HDL and possibly with increased CHD.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.