Genetic Cholesteryl Ester Transfer Protein Deficiency Is Extremely Frequent in the Omagari Area of Japan

Abstract

Low levels of HDL cholesterol have been clearly demonstrated to be associated with an increased incidence of coronary heart disease, strongly suggesting that HDL particles have an antiatherogenic function. However, little information has been available concerning the atherogenicity of a marked hyperalphalipoproteinemia (HALP). There is no agreement about whether plasma cholesteryl ester transfer protein (CETP) deficiency is associated with an antiatherogenic state or not, although this disorder was reported to be one of the major causes of marked HALP. In the current study, we have found a unique area (Omagari City, Akita Prefecture, Japan) where CETP deficiency caused by a G-to-A mutation at the 5' splice donor site of intron 14 in the CETP gene is extremely frequent. In Omagari City, the mutation was detected more than 20 times more frequently and the prevalence of a marked HALP with plasma HDL cholesterol > or = 2.58 mmol/L (100 mg/dL) was 5 to 10 times higher than in other areas of Japan. This discovery has made it possible to perform a large population-based study concerning the atherogenicity of a marked elevation of HDL cholesterol in a genetically more homogeneous population. There was a statistically significant U-shaped relationship between HDL cholesterol levels and the incidence of ischemic changes in electrocardiograms. In cases of HDL cholesterol < 1.81 mmol/L (70 mg/dL), the incidence increased in proportion to the levels of HDL cholesterol. The frequency of the CETP gene mutation was higher in patients with coronary heart disease than in healthy control subjects. In subjects aged > 80 years, the prevalence of both marked HALP and the intron 14 splicing defect was significantly lower than in the younger generation. The current study indicated for the first time that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome, suggesting the importance of reevaluation of the clinical significance and pathophysiology of a marked HALP.

Molecular Mechanisms of HDL-Cholesterol Elevation by Statins and Its Effects on HDL Functions

“…It is unclear whether this result was attributable to a class effect of CETP inhibitors or an adverse effect specific to torcetrapib 86,87) ; however, these studies revealed not only a significant decrease in LDL-C levels but also a marked increase in HDL-C levels, suggesting that HDL-C elevation does not necessarily provide an anti-atherosclerotic effect. Recently, the prospective Framingham survey showed that the low plasma CETP activity group had a greater increased risk for cardiovascular disease than the high CETP activity group 89) ; therefore, it cannot be ruled out that the mechanism of CETP inhibition may raise the risk for cardiovascular events, despite increasing HDL-C levels [90][91][92] . Probucol 93) , known as a lipid-lowering drug, is also a potent antioxidant and possesses antiatherogenic capability, despite decreasing the plasma HDL-C level.…”

Point Mutation (−69 G→A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects

“…The study of the Omagari area in Japan, where the Int14 ϩ1 G3 A mutation is extremely frequent, indicated that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome. 17 The Honolulu Heart Program demonstrated that the prevalence of coronary heart disease in men with CETP gene mutation was increased. 18 Therefore, genetic CETP deficiency appears to be an independent risk factor for coronary heart disease.…”

Effort Angina in a Middle-Aged Woman With Abnormally High Levels of Serum High-Density Lipoprotein Cholesterol A Case of Cholesteryl-Ester Transfer Protein Deficiency

“…2 Several types of genetic CETP deficiency are prevalent in certain ethnic populations including those from Germany, Finland, and Japan. [3][4][5][6] It has been suggested that in populations with CETP gene mutations, the overall prevalence of coronary artery disease is higher than among populations without these mutations, 4 although the mutations are associated with increased serum concentrations of HDL-C. In fact, in vitro studies have shown that in CETP deficiency large cholesteryl ester-rich HDL particles are defective in cholesterol efflux.…”