CETP deficiency from two prevalent mutations is identified as the first common genetic cause of high HDL cholesterol in the general population (J Clin Invest 1994)

Original title: Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol

J Clin Invest · 1 November 1994 · 9

Inazu A, Jiang XC, Haraki T, Yagi K, Kamon N, Koizumi J, Mabuchi H, Takeda R, Takata K, Moriyama Y

Screening 130 Japanese subjects with HDL cholesterol of 100 mg/dl or greater identified two additional cholesteryl ester transfer protein mutations beyond the previously described intron 14 A splice mutation (Int14 A): a novel intron 14 T-insertion (Int14 T), found in only one family, and the missense mutation D442G. Combined D442G and Int14 A allele frequencies rose from 9% to 43% across HDL-C strata of 60-79 to 120 mg/dl or greater, and in 236 general Japanese men heterozygote frequencies were 7% for D442G and 2% for Int14 A, together explaining about 10% of the total variance in HDL cholesterol. D442G homozygotes averaged 86 +/- 26 mg/dl versus 158 +/- 35 mg/dl for Int14 A homozygotes, making this the first common genetic deficiency state that explains a significant fraction of population HDL-C variation.

Original abstract

Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.