CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction.
Jakub J. Regieli,J. Wouter Jukema,Diederick E. Grobbee,John J. P. Kastelein,Jan Albert Kuivenhoven,Aeilko H. Zwinderman,Yolanda van der Graaf,Michiel L. Bots,Pieter A. Doevendans +8 more
Reads0
Chats0
TLDR
In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality, suggesting that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels.Abstract:
Aims Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB -B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes.
Methods and results We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB -B2 showed reduced CETP levels and higher HDL-cholesterol ( P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 ( P = 0.01) for atherosclerotic disease death, 1.53 ( P = 0.03) for ischaemic heart disease death, and 1.30 ( P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints.
Conclusion In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.read more
Citations
More filters
Journal ArticleDOI
Genetics of Coronary Artery Disease
TL;DR: Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk.
Journal ArticleDOI
HDL-targeted therapies: progress, failures and future
TL;DR: The HDL hypothesis is examined in molecular and mechanistic terms, focusing on features that have been addressed, those that remain to be tested, and potential new targets for future pharmacological interventions.
Journal ArticleDOI
Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome.
Gregory G. Schwartz,Anders G. Olsson,Christie M. Ballantyne,Phillip J. Barter,Ingar Holme,David Kallend,Lawrence A. Leiter,Eran Leitersdorf,John J.V. McMurray,Prediman K. Shah,Jean-Claude Tardif,Bernard R. Chaitman,Regina Duttlinger-Maddux,John Mathieson +13 more
TL;DR: Dal-OUTCOMES will determine whether CETP inhibition with dalcetrapib, added to current evidence-based care, reduces cardiovascular morbidity and mortality after ACS.
Journal ArticleDOI
Personalized medicine: hope or hype?
TL;DR: The utility and limitations of personal genomic data in three domains are discussed: pharmacogenomics, assessment of genetic predispositions for common diseases, and identification of rare disease-causing genetic variants.
Journal ArticleDOI
Beginning to Understand High-Density Lipoproteins
TL;DR: This article reconciles the classic view of high-density lipoproteins (HDL) associated with low risk for cardiovascular disease (CVD) with recent data casting doubt over the widely accepted beneficial role of HDL regarding CVD risk.
References
More filters
Journal ArticleDOI
Haploview: analysis and visualization of LD and haplotype maps
TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Journal ArticleDOI
A Proportional Hazards Model for the Subdistribution of a Competing Risk
Jason P. Fine,Robert Gray +1 more
TL;DR: This article proposes methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation, but these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function.
Journal Article
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Anders G. Olsson,Jjv McMurray,Gudmundur Thorgeirsson,C Spaulding,J Slattery,Kalevi Pyörälä,Ole Faergeman,RA Wright,Kåre Berg,Lars Wilhelmsen,Terje R. Pedersen,Tatu A. Miettinen,Harvey D. White,John Kjekshus,Michael Gnant +14 more
Journal ArticleDOI
Effects of Torcetrapib in Patients at High Risk for Coronary Events
Philip J. Barter,Mark J. Caulfield,Mats Eriksson,Scott M. Grundy,John J.P. Kastelein,Michel Komajda,Jose Lopez-Sendon,Lori Mosca,Jean-Claude Tardif,David D. Waters,Charles L. Shear,James H. Revkin,Kevin A. Buhr,Marian R. Fisher,Alan R. Tall,Bryan Brewer +15 more
TL;DR: Although there was evidence of an off-target effect of torcetrapib, it cannot rule out adverse effects related to CETP inhibition, and the trial was terminated prematurely because of an increased risk of death and cardiac events.
Journal ArticleDOI
Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease.
J. Tuomilehto,G. Vidgren,L. Toivanen,Eva Tuomilehto-Wolf,Kimmo Kohtamäki,J. Stengård,Paul Zev Zimmet,Ian R. Mackay,Mj Rowley,P. Koskela +9 more
TL;DR: Anti-GAD is a valuable early predictive marker and is associated with a very high risk for development of IDDM, and was measured in prediabetic sera from 151 women aged 20-39 years with newly diagnosed diabetes mellitus who had been identified through a nationwide diabetes register.