European Heart Journal Advance Access published online on October 28, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn465
CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction
1 Juliuscenter for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
2 Department of Cardiology, UMCU, Utrecht, The Netherlands
3 Department of Cardiology and Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, C5-P PO Box 9600, 2300 RC Leiden, The Netherlands
4 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
5 Durrer Institute for Cardiogenetic Research, Amsterdam, The Netherlands
6 Department of (Experimental) Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
7 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands
Received 13 April 2008; revised 7 September 2008; accepted 29 September 2008.
* Corresponding author. Tel: +31 71 5266695, Fax: +31 71 5266885, E-mail: j.w.jukema{at}lumc.nl
See page 2708 for the editorial comment on this article (doi:10.1093/eurheartj/ehn450)
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.
Key Words: Cholesteryl ester transfer protein • Lipoprotein metabolism • Pharmacogenetics • Risk factors • Prognosis
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