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.
Highlights
Plasma triglyceride (TG) levels are inversely related to high density lipoproteins (HDL)-cholesterol levels and subjects with high TG and low HDL cholesterol have increased coronary heart disease (CHD) risk
Because the transfer of the cholesteryl esters occurs as part of an exchange reaction with TG, the transfer rate is dependent on very low density lipoprotein TG, HDL-cholesterol (HDL-C), and cholesteryl ester transfer protein (CETP) concentrations
Epidemiological studies have shown high HDL levels to be protective against atherosclerosis [4,5,6], a recent study of Japanese-American men in the Honolulu Heart Program has shown that CETP deficiency is associated with increased prevalence of coronary heart disease (CHD), despite the resulting elevated HDL levels [7]
Summary
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. 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 g/ml for the II, IV and VV genotypes, respectively). 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.—Bruce, C., D. The difference in disease prevalence was found to be most marked in men with intermediate HDL levels (40–60 mg/ dl), and men with HDL cholesterol Ͼ60 mg/dl with or without CETP deficiency had a low CHD prevalence These results have suggested the importance of the dynamics of the cholesterol transport in plasma in addition to the lipoprotein profile as contributing to CHD risk. The two Abbreviations: aa405, amino acid 405; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; HDL, high density lipoprotein; HDL-C, HDL-cholesterol; LDL, low density lipoprotein; TG, triglyceride
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