Cholesteryl ester transfer protein polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events

M Leusink; N C Onland-Moret; F W Asselbergs; B Ding; S Kotti; N R van Zuydam; A C Papp; N Danchin; L Donnelly; A D Morris; D I Chasman; P A F M Doevendans; O H Klungel; P M Ridker; W H van Gilst; T Simon; F Nyberg; C N A Palmer; W Sadee; P van der Harst; P I W de Bakker; A de Boer; C Verstuyft; A H Maitland-van der Zee

doi:10.1038/clpt.2013.194

Cholesteryl ester transfer protein polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events

Clin Pharmacol Ther. 2014 Mar;95(3):314-20. doi: 10.1038/clpt.2013.194. Epub 2013 Sep 30.

Authors

M Leusink¹, N C Onland-Moret², F W Asselbergs³, B Ding⁴, S Kotti⁵, N R van Zuydam⁶, A C Papp⁷, N Danchin⁸, L Donnelly⁶, A D Morris⁶, D I Chasman⁹, P A F M Doevendans³, O H Klungel¹⁰, P M Ridker⁹, W H van Gilst¹¹, T Simon¹², F Nyberg¹³, C N A Palmer⁶, W Sadee⁷, P van der Harst¹⁴, P I W de Bakker¹⁵, A de Boer¹⁰, C Verstuyft¹⁶, A H Maitland-van der Zee¹⁰

Affiliations

¹ 1] Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands [2] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden.
⁵ Assistance Publique-Hopitaux de Paris, Hopital St. Antoine, URC-EST, Paris, France.
⁶ Centre for Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁷ Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
⁸ 1] Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France [2] Universite Paris-Descartes, Paris, France.
⁹ 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
¹¹ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹² 1] Assistance Publique-Hopitaux de Paris, Hopital St. Antoine, URC-EST, Paris, France [2] Department of Clinical Pharmacology, Universite Pierre et Marie Curie (Paris 6), Paris, France.
¹³ 1] Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden [2] Occupational and Environmental Medicine, Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁴ 1] Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁵ 1] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands [2] Harvard Medical School, Boston, Massachusetts, USA [3] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁶ 1] Assistance Publique-Hopitaux de Paris, Hopital Bicetre, Service de Genetique Moleculaire, Pharmacogenetique et Hormonologie, Le Kremlin Bicetre, France [2] Universite Paris-Sud, Le Kremlin-Bicetre, France.

PMID: 24080640
DOI: 10.1038/clpt.2013.194

Abstract

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cardiovascular Diseases / drug therapy
Cardiovascular Diseases / epidemiology*
Cardiovascular Diseases / genetics*
Cholesterol / blood*
Cholesterol Ester Transfer Proteins / genetics*
Cholesterol, HDL / blood
Cholesterol, LDL / blood
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Logistic Models
Male
Middle Aged
Myocardial Infarction / drug therapy
Myocardial Infarction / genetics
Odds Ratio
Polymorphism, Single Nucleotide / genetics
Randomized Controlled Trials as Topic
White People

Substances

CETP protein, human
Cholesterol Ester Transfer Proteins
Cholesterol, HDL
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cholesterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding