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

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(+l)-to-A mutation(Intl4 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C 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 exonl4/intronl4 boundary (Intl4 T) and a missense mutation (Asp'2 to Gly) within exon 15 (D442G).The Intl4 T mutation was only found in one family. However, the D442G and Intl4 A mutations were highly prevalent in subjects with HDL-C . 60 mg/dl, with combined allele frequencies of 9%, 12%, 21%, and 43% for HDL-C 60-79, 80-99, 100-119, and . 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Intl4 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 (Intl4 T and Intl4 A) was similar to that of Intl4 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Intl4 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86±26 mg/dl) were lower than in Intl4 A homozygotes (158±35 mgldl), 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 Intl4 A heterozygotes (69±15 mg/dl). Thus, the D442G mutation acts differently to the null mutations A portion of this paper was presented at the Asian-Pacific Congress on coronary heart disease risk factor held in Hong Kong, January 1994.

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

“…[13]. Screening analysis was performed for two prevalent mutations of CETP gene, Int14+1A and D442G, using RFLP method as previously described [9]. PCR was performed under the following conditions: 95 ○ C for 2 min; 30 cycles of 95 ○ C for 10 s; each optimized annealing temperature for 10 s; 72 ○ C for 30 s. We select 55-60 ○ C of annealing temperature on each primer.…”

“…Complete CETP deficiency presents extremely high HDL-cholesterol level and relatively low low density lipoprotein cholesterol (LDL-C) level [7]. About a half of HALP in Japan are caused by CETP gene mutations, and two prevalent mutations of D442G (allele frequency, 3.4% in Japanese population) and intron 14 splice donor site +1 G>A (Int14+1A) (0.8%) are well characterized [8,9]. The homozygote of D442G causes partial CETP deficiency by -54% and a moderate increase in HDL-C (mean, 96 mg/dL), while the homozygote of Int14+1A causes complete CETP deficiency and extremely high level of HDL-C (mean, 167 mg/dL) [10].…”

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

“…7,8 Several other single nucleotide polymorphisms (SNPs) in the CETP gene have been associated with interindividual variation in CETP plasma concentrations, HDL-C levels and risk of cardiovascular disease. [9][10][11][12][13][14][15][16][17][18][19][20] CETP deficiency associated with elevated HDL-C may, paradoxically, increase the risk for CHD in certain genotype/phenotype constellations. 21 However, in a large sib-pair linkage analysis, no relationship between allelic variation at the CETP locus and plasma HDL-C levels was detected, despite an association between CETP gene variation and plasma CETP concentrations.…”

A novel type of familial hypercholesterolemia: Double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene

“…Previously, we reported that the CETP gene mutations causing higher HDL-C levels are common in Japan [12]. However, there was no carrier of two common CETP gene mutations (c.1321+1G>A and c.1376A>G) among this family member.…”

“…We screened the study subjects for all coding region of PCSK9 and LDLRAP1 genes as candidate genes that could affect their lipid profile and clinical phenotype. In addition, we analyzed the two common mutations of the CETP gene (c.1321+1G>A, previously described as Int14A and c.1376A>G, previously described as D442G) among Japanese population as previously described [12].…”