Effect of apoE genotype on the hypolipidaemic response to pravastatin in an outpatient setting

Peña, Rocı́o; Lahoz, Carlos; Mostaza, José María; Jiménez, Javier; Subirats, Enric; Pintó, Xavier; Taboada, Manuel; López-Pastor, Angela

doi:10.1046/j.1365-2796.2002.00991.x

Cited by 51 publications

(26 citation statements)

References 31 publications

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“…43 Furthermore, the average decrease in LDL-C in our study was about similar for cerivastatin-and atorvastatin-treated patients, À36 and À38%, respectivley, and À24% LDL-C response to pravastatin in our study matched results of a Spanish outpatient study with 20% LDL lowering. 44 We deliberately did not choose to introduce a dose equivalence factor for our analysis, as others have chosen, 45 but tested for such an interaction. Since a significant interaction between LDL response and statin agent was confirmed in our study, this confounding effect was accounted for in the multivariate analysis of CETP haplotypes and LDL response.…”

Section: Limitationsmentioning

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: Limitationsmentioning

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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“…The consensus is that e4 carriers appear to have attenuated lipid-lowering response, and e2 carriers have enhanced response. 13,17,[58][59][60][61][62][63][64][65][66][67][68][69][70] Few studies have examined the effects of variations in genes encoding other apolipoproteins. There are reports that polymorphisms in APOB, the gene encoding the major structural protein in both LDL and triglyceride-rich lipoproteins, may alter LDLC response; whereas variation in the APOAI gene, encoding the major structural protein in HDL, may alter HDLC response.…”

mentioning

confidence: 99%

Clinical implications of pharmacogenomics of statin treatment

Mangravite¹,

Thorn

Krauss³

2006

Pharmacogenomics J

146

132

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“…It is also possible that subjects with the å4 allele are treated differently because some studies reported that their lipid response to statins is less favourable compared to the other genotypes [10][11][12][13][14]. However, other studies did not find such differences [15][16][17][18]. A lack of statistical power may also explain why we did not find a difference in effectiveness of statins in individuals with and without the å4 allele.…”

Section: Discussionmentioning

confidence: 83%

“…While other studies could not confirm these findings [15][16][17][18], in a substudy of the Scandinavian Simvastatin Survival Study (4S), subjects with the å4 allele with a history of myocardial infarction or angina pectoris had an almost two-fold higher risk of dying in a follow-up period of approximately 5.5 years compared to patients without an å4 allele. The increased risk of death was not accompanied by an increased risk of a major coronary event.…”

Section: Introductionmentioning

confidence: 99%

The effectiveness of hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) in the elderly is not influenced by apolipoprotein E genotype

et al. 2002

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aWe aimed to assess whether the effectiveness of statins in the prevention of myocardial infarction, stroke and total mortality is influenced by apolipoprotein E (apoE) genotype in an elderly population. We used data from the Rotterdam Study, a prospective population-based cohort study in the Netherlands which started in 1990 and included 7983 subjects aged 55 years and older. Subjects who were treated with cholesterol lowering drugs at baseline or with a serum total cholesterol > 6.5 mmol/l at baseline were included. We compared the incidence of myocardial infarction, stroke and total mortality in subjects who received > 2 years of statin treatment with that in subjects who had been treated for less than 2 years, and in untreated subjects, using a Cox proportional hazard model with cumulative statin use defined as time-dependent covariates. The adjusted relative risk of all-cause mortality was 0.79 [95% confidence interval (CI) 0.51-1.22] and of myocardial infarction and stroke 0.50 (95% CI 0.28-0.91) for subjects treated with statins for > 2 years compared to untreated subjects. The adjusted relative risks for subjects with the å4 allele were 0.91 (95% CI 0.45-1.84) for allcause mortality and 0.63 (95% CI 0.23-1.78) for myocardial infarction and stroke. In subjects without the å4 allele, adjusted relative risks were 0.71 (95% CI 0.41-1.24) for allcause mortality and 0.46 (95% CI 0.22-0.95) for myocardial infarction and stroke. We found a protective effect of statins on the risk of myocardial infarction and stroke that was independent of apoE genotype. The protective effect of statins on total mortality was not statistically significant, but did not seem to differ between subjects with different apoE genotypes.

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Effect of apoE genotype on the hypolipidaemic response to pravastatin in an outpatient setting

Cited by 51 publications

References 31 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

Clinical implications of pharmacogenomics of statin treatment

The effectiveness of hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) in the elderly is not influenced by apolipoprotein E genotype

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