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Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

The Pharmacogenomics Journal volume 3, pages 284–296 (2003)Cite this article

ABSTRACT

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 (P=0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P=0.04 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.

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Acknowledgements

We thank the LURIC study team and the laboratory staff at Ludwigshafen and Freiburg, Germany for their assistance in patient recruitment and laboratory analyses. Hubert Scharnagl, Freiburg, is acknowledged for the determination of CETP mass; furthermore, we thank the following employees from Genaissance Pharmaceuticals for their contributions to this project: Hongyu Zhao for statistical input and recommendation of the permutation-based, multiple comparison adjustment method; Cathy Stack and Bradley Dain for the statistical analysis; Mark Rabin, and Jennifer Bourne for genotyping; Chad Messer and Carol Reed for review of the manuscript and Anita Kaul for editorial assistance. This work has been partly funded by a research grant from Genaissance Pharmaceuticals, Inc., New Haven, CT, USA. Bernhard Boehm has been supported by the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Cooperation Unit of Pharmacogenomics/Applied Genomics, Ruprecht Karls-University, Heidelberg, Germany

    B R Winkelmann

  2. Department of Medicine, Division of Clinical Chemistry, Albert Ludwigs University, Freiburg, Germany

    M M Hoffmann, M Nauck & W März

  3. Genaissance Pharmaceuticals Inc., New Haven, CT, USA

    A M Kumar, K Nandabalan, R S Judson & G Ruaño

  4. Department of Internal Medicine, Division of Endocrinology and Diabetes, University of Ulm, Germany

    B O Boehm

  5. Department of Medicine, Division of Internal Medicine I, The College of Physicians and Surgeons, Columbia University, New York, NY, USA

    A R Tall

  6. Clinical Institute of Medical and Chemical Laboratory Diagnostics, University and General Hospital, Graz, Austria

    W März

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  1. B R Winkelmann
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Correspondence to B R Winkelmann.

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DUALITY OF INTEREST

BRW, ART have worked as a consultant for Genaissance Pharmaceuticals Inc. and have received honoraria for such work. WM, BOB have stock ownership in Genaissance Pharmaceuticals Inc. AMK, KN, RSJ, GR own stock or stock options in Genaissance Pharmaceuticals Inc. as part of their employee compensation plan.

Travel grants were provided by Genaissance Pharmaceuticals to BRW, MMH, and WM for meetings at the company head quarters (New Haven, CT U.S.A.), or to present results at a symposium (BRW). BRW, WM, MMH have been named as co-inventors on patent applications owned by Genaissance Pharmaceuticals Inc. in work related to this study.

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Winkelmann, B., Hoffmann, M., Nauck, M. et al. Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy. Pharmacogenomics J 3, 284–296 (2003). https://doi.org/10.1038/sj.tpj.6500195

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