Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins

Brown, Marie; Inazu, Akihiro; Hesler, C B; Agellon, Luis B.; Mann, Christopher; Whitlock, Mary E.; Marcel, Yves L.; Milne, Ross W.; Koizumi, Junji; Mabuchi, Hiroshi; Takeda, Ryoyu; Tall, Alan R.

doi:10.1038/342448a0

Cited by 452 publications

(206 citation statements)

References 25 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%

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%

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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“…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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“…It is well known that CETP promotes the transfer of cholesteryl esters from HDL to low-density lipoprotein, and individuals that are genetically deficient for CETP often have extremely high HDL levels. 20,21 In a recent GWAS on biochemical traits, BCAT1 is shown to be significantly associated with serum albumin concentration. 18 As albumin is correlated with HDL, 22 it is possible that CETP and BCAT1 interact in modulating the level of HDL-C. Figures 3 and 4 display the LD structures of CETP and BCAT1 estimated using the HDL data set.…”

Section: Application To the Hdl Data Setmentioning

confidence: 99%

Gene-based interaction analysis by incorporating external linkage disequilibrium information

Wang

Edmondson

et al. 2010

Eur J Hum Genet

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Gene-gene interactions have an important role in complex human diseases. Detection of gene-gene interactions has long been a challenge due to their complexity. The standard method aiming at detecting SNP-SNP interactions may be inadequate as it does not model linkage disequilibrium (LD) among SNPs in each gene and may lose power due to a large number of comparisons. To improve power, we propose a principal component (PC)-based framework for gene-based interaction analysis. We analytically derive the optimal weight for both quantitative and binary traits based on pairwise LD information. We then use PCs to summarize the information in each gene and test for interactions between the PCs. We further extend this gene-based interaction analysis procedure to allow the use of imputation dosage scores obtained from a popular imputation software package, MACH, which incorporates multilocus LD information. To evaluate the performance of the gene-based interaction tests, we conducted extensive simulations under various settings. We demonstrate that gene-based interaction tests are more powerful than SNP-based tests when more than two variants interact with each other; moreover, tests that incorporate external LD information are generally more powerful than those that use genotyped markers only. We also apply the proposed gene-based interaction tests to a candidate gene study on high-density lipoprotein. As our method operates at the gene level, it can be applied to a genome-wide association setting and used as a screening tool to detect gene-gene interactions.

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Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins

Cited by 452 publications

References 25 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

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

Gene-based interaction analysis by incorporating external linkage disequilibrium information

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