Increased High-Density Lipoprotein Levels Caused by a Common Cholesteryl-Ester Transfer Protein Gene Mutation

Inazu, Akihiro; Brown, Marie; Hesler, C B; Agellon, Luis B.; Koizumi, Junji; Takata, Koki; Maruhama, Yoshisuke; Mabuchi, Hiroshi; Tall, Alan R.

doi:10.1056/nejm199011013231803

Cited by 777 publications

(444 citation statements)

References 28 publications

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“…Such a concept is consistent with studies of genetic CETP deficiency in which heterozygotes have only slightly increased HDL-C, but homozygotes have a massive HDL-C elevation. 34 Of note is SNP7, wherein the substitution of C for G at amino acid 373 produced an increase in mass, yet the specific activity decreased. Whether these findings are due to chance or indicate a functional effect on CETP gene expression needs to be evaluated by further studies.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Serum TC and triglyceride (TG) were determined by enzymatic methods. Cholestest®N HDL (Sekisui Medical, Tokyo, Japan) was used for measurement of HDL-C, and Friedewald calculation was used for LDL-C estimation because a direct method for LDL-C has not been validated in CETP deficiency [7,11]. Serum apolipoprotein concentrations were determined by immunoassay.…”

Section: Biochemical Analysesmentioning

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].…”

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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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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“…5 " 7 A mutation in the cholesterol ester transfer protein (CETP) gene underlies genetically elevated levels of high density lipoprotein (HDL) cholesterol. 8 Mutations of the lipoprotein lipase (LPL) gene cause chylomicronemia and underlie hyperlipoproteinemia type I. 9 -11 In addition to the clinical lipoprotein disorders caused by these and other monogenic defects, there is evidence that concurrent inheritance of mutations at more than one genetic locus underlies a particular phenotype.…”

Section: -4 Othermentioning

confidence: 99%

Interaction between variant apolipoproteins C-II and E that affects plasma lipoprotein concentrations.

Hegele

Breckenridge

Cox

et al. 1991

Arterioscler Thromb

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The genes for apolipoprotein (apo) C-II, a cofactor for activation of lipoprotein lipase, and apo £, a ligand for receptor-mediated uptake of triglyceride-rich lipoproteins, are physically linked on chromosome 19ql3.1. In a large Caribbean Caucasian family, several individuals had clinical features of the complete absence of lipoprotein lipase activity and were homozygous for a DNA frameshift mutation of apo C-II, imparting functional inactivity to the mutant protein.Plasma from heterozygous carriers of this mutation, when compared with plasma from relatives who were noncarriers, had significantly diminished capacity to activate lipoprotein lipase in vitro. We also observed in heterozygotes for this mutation a wide range of serum lipid and lipoprotein levels. When age and sex were taken into account, the presence of a single apo E allele encoding the E4 isoform occurring in individuals with a single mutant apo C-II allele was strongly associated with higher levels of cholesterol, triglycerides, very low density lipoprotein cholesterol, and non-high density lipoprotein cholesterol when compared with those of relatives who carried neither or only one variant allele. This suggests that a single genetic mutation that usually has a recessive effect on lipoprotein metabolism can have an interactive effect on lipid phenotype when it is coinherited with a single mutation at another gene whose product affects the same metabolic pathway. (Arteriosclerosis and Thrombosis 1991;ll:1303-1309)

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Increased High-Density Lipoprotein Levels Caused by a Common Cholesteryl-Ester Transfer Protein Gene Mutation

Cited by 777 publications

References 28 publications

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

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

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

Interaction between variant apolipoproteins C-II and E that affects plasma lipoprotein concentrations.

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