Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype
- Rabea Asleh1,
- Shany Blum1,
- Shiri Kalet-Litman1,
- Jonia Alshiek1,
- Rachel Miller-Lotan1,
- Roy Asaf1,
- Wasseem Rock2,
- Michael Aviram2,
- Uzi Milman34,
- Chen Shapira56,
- Zaid Abassi7 and
- Andrew P. Levy1
- 1Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- 2Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel
- 3Clinical Research Unit, Clalit Health Services, Haifa and Western Galilee, Israel
- 4Department of Family Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- 5Clalit Health Services, Haifa and Western Galilee, Israel
- 6Lady Davis Carmel Medical Center, Haifa, Israel
- 7Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Corresponding author: Andrew P. Levy, alevy{at}tx.technion.ac.il
Abstract
OBJECTIVE—Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.
RESEARCH DESIGN AND METHODS—Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters.
RESULTS—Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.
CONCLUSIONS—Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008.
Clinical trial reg. no. NCT00314379, clinicaltrials.gov.
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- Accepted June 26, 2008.
- Received April 2, 2008.
- DIABETES
