Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction

Corbex, Marilys; Poirier, Odette; Fumeron, Frédéric; Betoulle, D; Evans, Alun; Ruidavets, Jean Bernard; Arveiler, Dominique; Luc, Gérald; Tiret, Laurence; Cambien, François

doi:10.1002/1098-2272(200007)19:1<64::aid-gepi5>3.0.co;2-e

Cited by 131 publications

(98 citation statements)

References 25 publications

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“…A total of 9 population-based studies qualified for inclusion: 4 prospective studies: the Framingham Offspring Study (FOS), 20 the Physicians' Health Study (PHS), 21 the Northwick Park Heart Study (NPHS), 22 and the Reykjavik study; 23 and 5 cross-sectional studies: the European Atherosclerosis Research Study (EARS), 24 Etude Cas-Témoins de l'Infarctus du Myocarde (ECTIM), 15,25,26 the Oulu Project Elucidating Risk of Atherosclerosis (OPERA), 11,27 a study performed by Arca et al, 28 and one performed by Corella et al 29 Databases with individual patient data were obtained from all studies except for the FOS and the study performed by Corella et al 20,29 ; thus these 2 studies were not included. We identified 3 randomized, double-blind, placebo-controlled trials of pravastatin treatment wherein a subanalysis had been performed on the role of the TaqIB polymorphism: the Regression Growth Evaluation Statin Study (REGRESS), 7 the Cholesterol And Recurrent Events trial (CARE), 9 and the West of Scotland Coronary Prevention Study (WOSCOPS).…”

Section: Resultsmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment

et al. 2005

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Background-Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. Methods and Results-A meta-analysis was performed on individual patient data from 7 large, population-based studies (each Ͼ500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, PϽ0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratioϭ0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearityϭ0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (Pϭ0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. Conclusions-The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy. (Circulation. 2005;111: 278-287.)

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Section: Resultsmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment

et al. 2005

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“…For instance, heavy drinkers who are homozygous for one particular CETP allele have a substantially reduced risk of myocardial infarction. 72 High CETP concentration has been associated with more rapid progression of coronary disease, and statin therapy is more effective in this subgroup, independent of baseline or on-treatment lipid levels, suggesting that the plasma CETP level may be an important determinant of the response to statins. 73 Statins reduce plasma CETP activity by Ϸ5% to 10% and cholesteryl ester transfer by Ϸ35%.…”

Section: Extension To Human Investigationmentioning

confidence: 99%

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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Abstract-Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol.Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by Ͼ50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ lipids Ⅲ metabolism Ⅲ statins A lthough lipid-lowering therapies now have the capability of reducing LDL cholesterol to levels recommended by the National Cholesterol Education Program (NCEP) guidelines in as many as 90% of treated patients, 1 the rate of cardiovascular events is reduced by only 20% to 35% in large, randomized trials. These data suggest that the LDL target set by NCEP guidelines may be too high. 1-5 Indeed, among patients with acute myocardial infarction, Ϸ15% have LDL levels Ͻ100 mg/dL on presentation.A complementary hypothesis is that there is a finite limit to the benefit of LDL lowering and that other non-LDL lipid risk factors must be managed for optimal outcomes. Indeed, epidemiological studies suggest that low HDL cholesterol may be a risk factor comparable in importance to high LDL and that the 2 risk factors are independent (Figure 1). 6,7 Although the mechanism by which HDL reduces the development of atherosclerosis has not been defined with certainty, acceleration of reverse cholesterol transport, antioxidant activity, and antiinflammatory action are likely to play central roles. 8 -10 In contrast to the ability of potent statins to reduce the level of LDL by Ͼ50%, however, no currently approved therapy increases HDL by a comparable magnitude. The most potent, currently available HDL-raising therapy is nicotinic acid. This therapy also has a multitude of other antiatherosclerotic effects on the levels of LDL and triglycerides, lipid oxidation, and endothelial function. 11 Combination therapy with a statin has been reported to increase HDL levels by Ϸ30% 12 and to decrease cardiac events...

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“…Nine of these associations were confirmed in individual genotyping (P Ͻ 0.05) and found to be distributed across the length of the gene. Among them are rs1800775, a promoter SNP, rs708272, an SNP in intron 2 (known as TaqIB), and rs5882, an amino acid substitution in exon 14 (known as I405V), all of which have been reported to be associated with HDL levels (17,18,22).…”

Section: Preparation Of Single-stranded Template For Massextend (Seque-mentioning

confidence: 99%

Association testing by DNA pooling: An effective initial screen

Bansal

Boom²,

Kammerer³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

145

116

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With an ever-increasing resource of validated single-nucleotide polymorphisms (SNPs), the limiting factors in genome-wide association analysis have become genotyping capacity and the availability of DNA. We provide a proof of concept of the use of pooled DNA as a means of efficiently screening SNPs and prioritizing them for further study. This approach reduces the final number of SNPs that undergo full, sample-by-sample genotyping as well as the quantity of DNA used overall. We have examined 15 SNPs in the cholesteryl ester transfer protein (CETP) gene, a gene previously demonstrated to be associated with serum high-density lipoprotein cholesterol levels. The SNPs were amplified in two pools of DNA derived from groups of individuals with extremely high and extremely low serum highdensity lipoprotein cholesterol levels, respectively. P values <0.05 were obtained for 14 SNPs, supporting the described association. Genotyping of the individual samples showed that the average margin of error in frequency estimate was Ϸ4% when pools were used. These findings clearly demonstrate the potential of pooling techniques and their associated technologies as an initial screen in the search for genetic associations.A ssociation testing may be regarded as a comparison of allele frequency between cases and controls, in which a statistically significant difference is used to implicate a locus in a disease etiology. The methodology relies on the investigator testing either the causal variant itself or a marker in linkage disequilibrium (LD) with the causal variant. It is now well known that the distance over which LD extends is highly variable, not only between populations (1-3) but also across genomic regions (4, 5). A comprehensive genome scan by association analysis is therefore likely to require tens or hundreds of thousands of markers (6, 7).To date, we have performed validation experiments on Ϸ200,000 putative single-nucleotide polymorphisms (SNPs) from the public domain, and the confirmation rate is Ϸ60% in a Caucasian sample (unpublished results). The theoretical advantages of analyzing these SNPs by an association rather than by a linkage approach are clear (8). The reality, however, is hindered by the expense of generating the necessarily large number of genotypes. The use of pooled DNA has been offered as an alternative in the case of qualitative traits (9-11), but practical extensions to quantitative traits have not been presented thus far.To evaluate the applicability of pooled samples, SNPs in the cholesteryl ester transfer protein (CETP) gene were tested for association by using a pair of pools containing DNA from individuals with low and high serum high-density lipoprotein cholesterol (HDL-C) levels, respectively. CETP is known to play an essential role in reverse cholesterol metabolism. It is believed to mediate the exchange of cholesteryl ester in HDL-C for triglyceride in low-density lipoprotein (LDL) or very low-density lipoprotein (VLDL) (12)(13)(14).

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Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction

Cited by 131 publications

References 25 publications

Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment

Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

Association testing by DNA pooling: An effective initial screen

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