Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.
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.


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.
Asleh
Rabea
R
Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Blum
Shany
S
Kalet-Litman
Shiri
S
Alshiek
Jonia
J
Miller-Lotan
Rachel
R
Asaf
Roy
R
Rock
Wasseem
W
Aviram
Michael
M
Milman
Uzi
U
Shapira
Chen
C
Abassi
Zaid
Z
Levy
Andrew P
AP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use
D000975:Antioxidants; D006242:Haptoglobins; D008075:Lipoproteins, HDL; D014810:Vitamin E