A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins.

Takahashi, Kazuo; Jiang, Xian‐Cheng; Sakai, Naohiko; Yamashita, Shizuya; Hirano, Ken‐ichi; Bujo, Hideaki; Yamazaki, Hiroyuki; Kusunoki, Jun; Miura, Tadashi; Kussie, Paul

doi:10.1172/jci116802

Cited by 131 publications

(85 citation statements)

References 24 publications

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“…Many CETP gene mutations are reported, such as nonsense mutations (n=8), splice junction mutations (n=6), missense mutations (n=5), small gene deletions and insertions (n=4), promoter mutations (n=2) and others (n=1) (Fig.6) [8,9,20,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. In the present study, we identified c.653_654delGGinsAAAC and c.658G>A from several subjects with HALP, and it suggests that nonsense and splicing defect mutations account for the majority of CETP gene mutations.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Ohtani

Inazu

Noji

et al. 2012

Clinica Chimica Acta

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Background: The half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1 G>A), some rare CETP mutations are found in Japanese HALP subjects.Methods: CETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector.Results: Each of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1 G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells.Conclusions: Three novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations responsible for mild-to-moderate or marked HALP, respectively.3

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ohtani

Inazu

Noji

et al. 2012

Clinica Chimica Acta

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“…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

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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...

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Winkelmann¹,

Hoffmann

Nauck

et al. 2003

Pharmacogenomics J

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Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were determined in 98 patients with untreated dyslipidemias and analyzed for associations with plasma CETP and plasma lipids before and during statin treatment. Individual CETP SNPs and haplotypes were both significantly associated with CETP enzyme mass and activity. However, only certain CETP haplotypes, but not individual SNPs, significantly predicted the magnitude of change in HDL cholesterol (HDL-C) and triglycerides. After adjusting for covariates and multiple testing, the TTCAAA haplotype showed a gene-dose effect in predicting the HDL-C increase (P¼0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P¼0.04 both). This is the first study to demonstrate that SNP haplotypes derived from allelic SNP combinations in the CETP gene were more informative than single SNPs in predicting the response to lipid-modifying therapy with statins. The Pharmacogenomics Journal (2003) 3, 284-296, doi:10.1038/sj.tpj.6500195Keywords: cholesteryl ester transfer protein; HDL-cholesterol; triglycerides; haplotype; single nucleotide polymorphism; statin INTRODUCTION Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins and plays a central role in high-density lipoprotein (HDL) metabolism. CETP transfers cholesteryl esters associated with HDL to triglyceride-rich lipoproteins, facilitating the clearance of cholesteryl esters from plasma. 1 Although the potential contribution of CETP to reverse cholesterol transport suggests an antiatherogenic mode of action, knowledge of the physiologic role of CETP in lipoprotein metabolism remains incomplete. The overall effect of CETP on atherogenesis may vary depending on both metabolic context and molecular variation in the CETP gene. 2 Investigations of associations between genetic variants in CETP and cardiovascular phenotypes are numerous, but often conflicting in their findings. The Taq1B polymorphism of the CETP gene has been associated with plasma levels of CETP and HDL cholesterol (HDL-C) and with the risk of coronary heart disease (CHD). 3,4 The Taq1B polymorphism has also been shown to serve as a marker of lipoprotein response to dietary intervention. 5,6 Other studies have demonstrated a link between the CETP I405V gene polymorphism and HDL-C, but not with response to diet. 7,8 Several other single nucleotide polymorphisms (SNPs) in the

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A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins.

Cited by 131 publications

References 24 publications

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

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

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

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

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