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A common CETP gene splicing mutation causes markedly elevated HDL in Japan without excess atherosclerosis (N Engl J Med 1990)
Original title: Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation
Having previously found a Japanese family with high HDL and CETP deficiency from a gene splicing defect, the authors screened 11 additional Japanese families with high HDL using CETP radioimmunoassay and DNA analysis, finding the identical mutation, on the same haplotype, in four families from three regions of Japan. The ten homozygotes for CETP deficiency had moderate hypercholesterolemia, markedly increased HDL cholesterol (4.24 mmol/l) and apoA-I, and decreased LDL cholesterol (1.99 mmol/l) and apoB, while the 20 heterozygotes had moderately increased HDL cholesterol and apoA-I and a raised HDL2 to HDL3 ratio (1.5 versus 0.7 in unaffected relatives). The mutation was absent in six unrelated Americans with elevated HDL. The authors conclude CETP deficiency is a frequent, likely founder-effect cause of high HDL in Japan, that CETP normally regulates HDL2 levels, and that these families showed no premature atherosclerosis despite a lipoprotein profile potentially antiatherogenic and possibly associated with increased life span.
Original abstract
Background And Methods: The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis.
Results: We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD], 7.01 +/- 0.83 mmol per liter), markedly increased levels of HDL cholesterol (4.24 +/- 1.01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1.99 +/- 0.80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1.5 +/- 0.8 vs. 0.7 +/- 0.4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States.
Conclusions: CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.