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Papers In Press, published online ahead of print September 1, 2007
J. Lipid Res., doi:10.1194/jlr.M700076-JLR200

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Journal of Lipid Research, Vol. 48, 2072-2078, September 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients

Jonathan B. Singer^1,*, Hallvard Holdaas, Alan G. Jardine, Bengt Fellstrøm^**, Ingrid Os, Georgina Bermann, Joanne M. Meyer^* on behalf of the Assessment of Lescol in Renal Transplantation (ALERT) Study Investigators

^* Clinical Pharmacogenetics, Novartis Institutes for Biomedical Research, Cambridge, MA
Medical Department, Rikshospitalet, Oslo, Norway
Department of Medicine and Therapeutics, University of Glasgow, Glasgow, United Kingdom
^** University Hospital, Uppsala, Sweden
School of Medicine, University of Oslo, Oslo, Norway
Biostatistics and Statistical Reporting, Novartis Pharma AG, Basel, Switzerland

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one table.

Published, JLR Papers in Press, June 11, 2007.

¹ To whom correspondence should be addressed. e-mail: jonathan.singer{at}novartis.com

ABSTRACT

The Assessment of Lescol in Renal Transplantation clinical trial demonstrated the efficacy of fluvastatin in reducing cardiovascular (CV) disease in renal transplant recipients. The study included a voluntary pharmacogenetic component, enrolling 1,404 patients, which allowed association testing of baseline measures and longitudinal analysis of the 707 fluvastatin-treated and 697 placebo-treated individuals. A candidate gene approach, examining 42 polymorphisms in 18 genes, was used to test for association between selected polymorphisms and major adverse cardiac events, graft failure, change in LDL and HDL cholesterol, and baseline LDL and HDL cholesterol. Reported associations between cholesteryl ester transfer protein (CETP) and baseline HDL cholesterol were replicated, with four previously implicated single nucleotide polymorphisms significantly associated in males and one in females; tests of reported associations between CETP and CV disease yielded varying results. We found no evidence for genetic factors affecting fluvastatin response. Polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) previously reported to affect the efficacy of pravastatin did not show a similar effect on the reduction of LDL cholesterol by fluvastatin.

Supplementary key words pharmacogenetics • association • cholesteryl ester transfer protein • 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Abbreviations: ALERT, Assessment of Lescol in Renal Transplantation; CETP, cholesteryl ester transfer protein; CV, cardiovascular; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; MACE, major adverse cardiac events; MI, myocardial infarction; PRINCE, Pravastatin Inflammation/CRP Evaluation; RTR, renal transplant recipient; SNP, single nucleotide polymorphism

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