Sex-Dependent Association of a Genetic Polymorphism of Cholesteryl Ester Transfer Protein with High-Density Lipoprotein Cholesterol and Macrovascular Pathology in Type II Diabetic Patients

Durlach, A.; Clavel, Christine; Girard-Globa, Anik; Durlach, V.

doi:10.1210/jcem.84.10.6064

Cited by 33 publications

(29 citation statements)

References 29 publications

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“…In the Framingham cohort, men with the B2 allele had a lower CHD risk (14). In line with these results, it has been observed that male patients with type 2 diabetes and the CETP B2B2 genotype may have a decreased risk for coronary artery disease (CAD) pro-gression (11). Recently, a new polymorphism was described, located at Ϫ629 (A-629C) in the promoter region of the CETP gene.…”

mentioning

confidence: 69%

Common Cholesteryl Ester Transfer Protein Gene Polymorphisms and the Effect of Atorvastatin Therapy in Type 2 Diabetes

Venrooij

Stolk

Banga³

et al. 2003

Diabetes Care

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OBJECTIVE -The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes.RESEARCH DESIGN AND METHODS -We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes. RESULTS -CETPTaqIB and A-629C polymorphisms were tightly concordant (P Ͻ 0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 Ϯ 0.2 vs. 1.11 Ϯ 0.2 mmol/l, P Ͻ 0.05), higher CETP mass (2.62 Ϯ 0.8 vs. 2.05 Ϯ 0.4 mg/l, P Ͻ 0.001), and slightly increased, though not significant, plasma TGs (2.7 Ϯ 1.05 vs. 2.47 Ϯ 0.86, P ϭ 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both vs. placebo P Ͻ 0.001, A10-A80 P Ͻ 0.001). CETP mass and activity were strongly correlated (r ϭ 0.854, P Ͻ 0.0001). CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1%, B2B2 0.5%; P Ͻ 0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B2B2 18.4%; P ϭ 0.08), and CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P ϭ 0.27, NS). Similar results were obtained for the A-629C polymorphism.CONCLUSIONS -In conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy. Diabetes Care 26:1216 -1223, 2003C holesteryl ester transfer protein (CETP) plays a key role in lipoprotein metabolism, promoting the exchange of triglycerides (TGs) and cholesteryl esters (CEs) between lipoprotein particles, resulting in both a net transfer of CEs from HDL cholesterol to apolipoprotein B (apoB)-containing lipoproteins and a subsequent uptake of cholesterol by hepatocytes (1). This reverse cholesterol transport is considered an antiatherogenic phenomenon. However, in the presence of elevated TG concentrations, an increased CE/TG transfer may induce the formation of smaller-sized LDL particles and decreased HDL cholesterol levels (2,3), providing a proatherogenic property of the action of CETP (4,5). The lipoprotein profile in type 2 diabetes is characterized by the presence of increased TG-rich lipoprotein remnant particles, small dense LDL particles, and decreased levels of HDL cholesterol. These conditions favor an increased transfer of CE from HDL (6 -8). However, reports on CETP mass and activity in type 2 diabetes appear to be conflicting (9 -11). These differences may be explained by differences in baseline plasma TG concentrations in the study populations (6,12).Genetic heterogeneity at the CETP gene locus is associated with plasma CETP activity and HDL cholesterol levels. The most frequently studi...

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confidence: 69%

Common Cholesteryl Ester Transfer Protein Gene Polymorphisms and the Effect of Atorvastatin Therapy in Type 2 Diabetes

Venrooij

Stolk

Banga³

et al. 2003

Diabetes Care

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“…In support of this hypothesis, several groups have reported associations between mutations at CETP and cardiovascular disease risk itself. 37,38 A few previously published linkage studies have provided only nominal or suggestive evidence that variation in HDL-C is influenced either by a QTL in this region of chromosome 16 or by the 2 candidate loci, CETP or LCAT. A sib-pair linkage analysis of HDL-C concentration data for 30 coronary artery disease families 2 yielded suggestive evidence of linkage (LODϭ2.06), with a QTL linked to D16S313, a marker locus that maps to within 6 cM of the marker loci nearest our multipoint peak.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

Mahaney

Almasy

Rainwater

et al. 2003

ATVB

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Objective-We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS). Methods and Results-After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)ϭ3.73 (Pϭ0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LODϭ2.73, Pϭ0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). Key Words: HDL Ⅲ genome screen Ⅲ linkage Ⅲ heritability Ⅲ Mexican Americans W e previously reported a major locus influencing quantitative variation in plasma HDL cholesterol (HDL-C) levels in Mexican-American families from the San Antonio Family Heart Study (SAFHS). 1 This major-locus effect, accounting for 56% to 67% of the additive genetic variance in HDL-C in those families, was detected only when the effects of age and sex terms plus plasma levels of apolipoprotein A-I (apo A-I) and triglycerides (TG), exogenous sex hormone use, and menopause status were included in the complex segregation analysis model for the trait. In males and females, respectively, the major locus accounted for 11% and 4% of the total phenotypic variance in plasma total HDL-C levels and for 55% and 21% of the residual phenotypic variance, ie, the proportion of the phenotypic variance not attributable to the effects of covariates. Because genotype data were not available for a whole-genome linkage screen when this major locus first was detected, we attempted to identify a locus responsible for this effect by means of combined segregation and linkage analysis with genotype data for likely candidate loci. Results of these analyses 1 were both definitive and negative, excluding linkage between the major locus for residual HDL-C and structural loci for several proteins of lipoprotein metabolism, namely, APOA-I, APOB, LDLR, LIPC, and LPL, on chromosomes 11q, 2p, 19p, 15q, and 8p, respectively. Conclusions-A QTL influencing plasma levels of HDL-C inAlthough subsequent analyses of data from the SAFHS and other studies have mapped quantitative trait loci (QTLs) for HDL-C-related measures to chromosome 1q 2 , chromosome 13q, 3,4 and chromosome 9p 5 , other reports localize HDL-Crelated QTLs to some chromosomal regions containing candidate loci ...

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“…Progression of atherosclerosis was found to be significantly associated (P Ͻ 0.03) with the B1 allele in a study of 807 Dutch men with CAD (64). French male diabetics are at increased risk of coronaropathies (P ϭ 0.025) with the B1 allele, while there was no effect in females (67). Finns with gall bladder disease have a higher risk of gallstones with the B1 allele (76), and Japanese diabetics have a higher likelihood of microangiopathy (P ϭ 0.009) with the B1 allele (73).…”

Section: Wild-type Proteinmentioning

confidence: 99%

Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease

Boekholdt

Thompson

2003

Journal of Lipid Research

153

117

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Since the identification of cholesteryl ester transfer protein (CETP), its role in the modulation of HDL levels and cardiovascular disease has been debated. With the early detection of genetic variants followed by the finding of families deficient in CETP, genetic studies have played a large role in the attempts to understand the association of CETP with lipids and disease; however, results of these studies have often led to disparate conclusions. With the availability of a greater variety of genetic polymorphisms and larger studies in which disease has been examined, it is now possible to compare the breadth of CETP genetic studies and draw better conclusions. The most broadly studied polymorphism is TaqIB for which over 10,000 individuals have been genotyped and had HDL levels determined. When these studies are subjected to a meta-analysis, the B2B2 homozygotes are found to have higher HDL levels than B1B1 homozygotes (0.12 mmol/l, 95% CI ‫؍‬ 0.11-0.13, P Ͻ 0.0001). A similar analysis of the I405V polymorphism yields 0.05 mmol/l higher HDL levels in 405VV homozygotes than in 405II homozygotes (95% CI ‫؍‬ 0.03-0.07, P Ͻ 0.0001). The implications of these studies for cardiovascular disease will be addressed. -Boekholdt, S. M., and J. F. Thompson. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J. Lipid Res. 2003. 44: 1080-1093.

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Sex-Dependent Association of a Genetic Polymorphism of Cholesteryl Ester Transfer Protein with High-Density Lipoprotein Cholesterol and Macrovascular Pathology in Type II Diabetic Patients

Cited by 33 publications

References 29 publications

Common Cholesteryl Ester Transfer Protein Gene Polymorphisms and the Effect of Atorvastatin Therapy in Type 2 Diabetes

Common Cholesteryl Ester Transfer Protein Gene Polymorphisms and the Effect of Atorvastatin Therapy in Type 2 Diabetes

A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease

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