Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects

Sakai, Naohiko; Yamashita, Shizuya; Hirano, Ken‐ichi; Menju, Masakazu; Arai, T.; Kobayashi, Kazushi; Ishigami, Masato; Yoshida, Yu; Hoshino, Tadashi; Nakajima, Noriaki; Kameda‐Takemura, Kaoru; Matsuzawa, Yūji

doi:10.1016/0021-9150(94)05477-z

Cited by 54 publications

(36 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the preliminary study, similar results were obtained in het- erozygous young adults with D442G (n ϭ 8). Most previous clinical studies on D442G mutation were conducted in older subjects with a mean age of more than 50 y (14,15,23). As mentioned previously, plasma HDL levels are regulated by many environmental factors as well as genetic factors.…”

Section: Discussionmentioning

confidence: 99%

Effect of a Common Mutation (D442G) of the Cholesteryl Ester Transfer Protein Gene on Lipids and Lipoproteins in Children

et al. 2001

View full text Add to dashboard Cite

Cholesteryl ester transfer protein (CETP) is thought to regulate plasma HDL. Patients with CETP deficiency caused by mutation of the CETP gene [D442G; a missense mutation (Asp4423 Gly)] have been reported to show high plasma HDL levels. However, there are no data available on children with D442G. To determine the effects of plasma CETP and CETP gene mutation (D442G) on lipids and lipoproteins in children, we screened children by PCR and restriction fragment length polymorphism analysis of the CETP gene. Plasma lipids, apolipoproteins, and CETP mass levels were also determined. In the current study, 22 children with D442G were found (21 heterozygotes and a homozygote). A homozygous child showed high plasma HDL level and very low plasma CETP mass. In heterozygous children, plasma concentrations of HDL cholesterol, apo A-I and apo A-II were not increased, whereas plasma CETP mass was significantly decreased. Plasma CETP mass in heterozygous children was correlated with plasma concentrations of total cholesterol, LDL cholesterol, and apo B. Plasma CETP mass in children without D442G was not correlated with the plasma concentration of any lipid or apolipoprotein. All of these data suggest that the D442G mutation, by itself, might not affect HDL metabolism in children. The CETP mass required for efficient HDL-cholesteryl ester clearance in children may be less than that in older subjects. Esterification of cholesterol from peripheral tissues and subsequent transfer of CE from HDL to other lipoproteins are key steps in reverse cholesterol transport, i.e. transport from peripheral cells to the liver for excretion (1, 2). In humans, extracellular cholesterol is esterified by the action of LCAT, and the CE generated is transferred to the liver by two known pathways: 1) uptake of HDL particles by the liver (3, 4), and 2) uptake of HDL CE by LDL receptor in the liver via transfer of HDL-CE to VLDL and LDL, in a process mediated by CETP (1, 2, 5). Most LCAT and CETP are associated with HDL particles in human plasma (6, 7). Cholesterol esterification in HDL by LCAT increases the size of HDL particles, and the transfer of CE from HDL particles reduces the size of HDL. Thus, the size of HDL particles reflects the net rate of CE generation on and CE transfer from HDL particles. Furthermore, we have shown in previous studies that the function of HDL, as well as the particle size, is strongly affected in the presence of LCAT or CETP deficiency (8, 9). These findings, taken together, suggest that LCAT and CETP play a central role in maintaining the antiatherogenic nature of HDL.To date, several common polymorphisms have been reported in the CETP gene (10 -12). Most are located within intronic regions and do not appear to affect either the secretion or the function of CETP. Two mutations, an intron 14 splice donor site mutation (Int14A) and a missense mutation within exon 15 (D442G), have been reported in Japanese subjects with high HDL-C levels (Ͼ100 mg/dL) (13-15). These mutations affect the structure and function of CETP and are ...

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of a Common Mutation (D442G) of the Cholesteryl Ester Transfer Protein Gene on Lipids and Lipoproteins in Children

et al. 2001

View full text Add to dashboard Cite

show abstract

“…These 2 mutations are relatively frequent in the Japanese population. 5,7,8,10 Patients with CETP deficiency have moderate hypercholesterolemia and markedly increased levels of HDL cholesterol. The lipoprotein abnormalities in CETP deficiency are also characterized by the presence of polydisperse LDL enriched with triglycerides and large, CE-rich HDL particles.…”

Section: Abstract-cholesteryl Ester Transfer Protein (Cetp) Transfersmentioning

confidence: 99%

“…The PCR amplification was performed with pairs of primers: 5Ј-CAGGGGCTCATTGTGGTGCT-3Ј (sense), 5Ј-GACCACAGGGAGTCAGCCAG-3Ј (antisense) for G181X 22 ; 5Ј-GGACTTTACTCCACCCACC-3Ј (sense), 5Ј-GGATTGGGGTA-CGTGAGTAAAC-3Ј (antisense) for Q309X 23 and Int10 ϩ2 T3 G 24 ; 5Ј-CTTCTGTGCTCCAGGGAGGACTCA-3Ј (sense), 5Ј-CAGTTTC-CCCTCCAGCCCACACAT-3Ј (mismatch primer, antisense) for Int14 ϩ1 G3 A 4 -6 and Int14 ϩ3 T ins 7 ; and 5Ј-CAGCAAAGGCGTGA-GCCTGGTC-3Ј (mismatch primer, sense), 5Ј-CCCAGGAATCCT-GTCTGGGCC-3Ј (antisense) for D442G. 9,10 The amplified PCR products were digested with the restriction enzymes MaeIII for G181X, DdeI for Q309X, MaeIII for Int10 ϩ2 T3 G, NdeI for Int14 ϩ1 G3 A, HpaI for Int14 ϩ3 T ins, and SalI for D442G at 37°C for 3 hours. After digestion, the reaction mixture was electrophoresed on a 10% polyacrylamide gel.…”

Section: Mutation Screening Using Pcr-restriction Fragment Length Polmentioning

confidence: 99%

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

Nagano

Yamashita

Hirano

et al. 2001

ATVB

Self Cite

View full text Add to dashboard Cite

Abstract-Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo)B-containing lipoproteins and plays a crucial role in reverse cholesterol transport, which is a major protective system against atherosclerosis. Genetic CETP deficiency is the most common cause of a marked hyperalphalipoproteinemia (HALP) in the Japanese, and various mutations have been identified in the coding region as well as in the exon/intron boundaries in the CETP gene. In the present study, we identified a novel mutation in the promoter region of the CETP gene. This mutation was a G-to-A substitution at the Ϫ69 nucleotide of the promoter region (Ϫ69 G3 A), corresponding to the second nucleotide of the PEA3/ETS binding site (CGGAA) located upstream of the putative TATA box. Four (2.0%) of 196 unrelated subjects with a marked HALP (HDL cholesterol Ն2.59 mmol/Lϭ100 mg/dL) were revealed to be heterozygous for the Ϫ69 G3 A mutation, and the allelic frequency of the mutant was 0.0102 in the subjects with a marked HALP. The subjects with the Ϫ69 G3 A mutation had low plasma CETP levels. Reporter gene assay showed that this mutation markedly reduced the transcriptional activities in HepG2 cells (8% of wild type). These results suggested that this mutation would be dominant negative. In conclusion, a novel Ϫ69 G3 A mutation in the CETP gene causes the decreased transcriptional activity leading to HALP. Key Words: cholesteryl ester transfer protein deficiency Ⅲ hyperalphalipoproteinemia Ⅲ mutation Ⅲ promoter Ⅲ PEA3/ETS binding site C holesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyzes the transfer of cholesteryl ester (CE) from HDL to apolipoprotein (apo) B-containing lipoproteins and is one of the major determinants of plasma HDL cholesterol levels. 1-3 Genetic CETP deficiency is the most common cause of hyperalphalipoproteinemia (HALP) in the Japanese. 4 -10 It has been demonstrated that a G-to-A substitution at the 5Ј splice donor site of intron 14 (Int14 ϩ1 G3 A) and a missense mutation of exon 15 (D442G) in the CETP gene are common mutations associated with HALP. These 2 mutations are relatively frequent in the Japanese population. 5,7,8,10 Patients with CETP deficiency have moderate hypercholesterolemia and markedly increased levels of HDL cholesterol. The lipoprotein abnormalities in CETP deficiency are also characterized by the presence of polydisperse LDL enriched with triglycerides and large, CE-rich HDL particles. 11-14 These results indicated that CETP is involved in the regulation of plasma lipoproteins by modulating both the quantity and quality of each lipoprotein particle.In addition, CETP plays an important role in reverse cholesterol transport from peripheral tissues to the liver. 15,16 Recently, CETP deficiency has been thought to be a proatherogenic state because of the crucial role of CETP in reverse cholesterol transport despite high HDL cholesterol levels. The study of the Omagari area in Japan, where the Int14 ϩ1 G3 A mutation is extremely frequent...

show abstract

“…The -629C/A promoter polymorphism (rs1800775), on the contrary affects 50 % of CETP activity and has showed HDL-C raising effect [11]. There have been other polymorphisms in the CETP (D442G) [12] and LIPC genes (-2T/C) [13] that have been associated with CAD risk. We hypothesize that polymorphisms in these genes may be responsible for high prevalence of atherogenic dyslipidemia (sdLDL and reduced HDL) and could be important determinants of CAD risk in our population.…”

Section: Introductionmentioning

confidence: 99%

Association of CETP and LIPC Gene Polymorphisms with HDL and LDL Sub-fraction Levels in a Group of Indian Subjects: A Cross-Sectional Study

Todur

Ashavaid

2012

Ind J Clin Biochem

View full text Add to dashboard Cite

There is an increasing interest to understand the molecular basis of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) subfractions and their association with coronary artery disease (CAD). The formation of these subfractions is greatly influenced by hepatic lipase (HL) and cholesteryl ester transfer protein (CETP) enzymes. To identify genetic markers influencing LDL and HDL subfractions and their role in CAD we performed a case-control genetic association study on 117 healthy controls and 119 angiographically verified CAD patients. Biochemical analysis was performed using standard assays. HDL-C and LDL-C subfractions were estimated using precipitation methods. Genotyping of C-514T (rs1800588) in the LIPC gene for HL and I405V (rs5882) in the CETP gene was done using PCR-based restriction enzyme analysis and sequencing. Both the polymorphisms were not associated with CAD. The C-514T was associated with increased HDL 3 -C levels in controls (P = 0.049). The I405V polymorphism was found to be associated with low levels of small dense, LDL (P = 0.038). A multiple regression analysis showed that the effects were dependent on gender and triglyceride levels. We conclude that these polymorphisms are not associated with CAD but are important determinants of HDL-C and small dense LDL particles in our population.

show abstract

Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects

Cited by 54 publications

References 25 publications

Effect of a Common Mutation (D442G) of the Cholesteryl Ester Transfer Protein Gene on Lipids and Lipoproteins in Children

Effect of a Common Mutation (D442G) of the Cholesteryl Ester Transfer Protein Gene on Lipids and Lipoproteins in Children

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

Association of CETP and LIPC Gene Polymorphisms with HDL and LDL Sub-fraction Levels in a Group of Indian Subjects: A Cross-Sectional Study

Contact Info

Product

Resources

About