Correction of HDL dysfunction in individuals with Diabetes and the Haptoglobin 2-2 genotype

Abstract

Objective. Pharmacogenomics is a key component of personalized medicine. ICARE, a prospective placebo controlled study, recently demonstrated vitamin E could dramatically reduce CVD in individuals with Diabetes Mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype (40% of DM individuals). However, due to the large number of clinical trials which failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in DM 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 DM interact to promote HDL oxidative modification and dysfunction.

Research Design and Methods. Hemoglobin and lipid peroxides were assessed in HDL isolated from DM 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 DM humans and in Hp 1-1 and Hp 2-2 DM mice assessed the ability of vitamin E to favorably modify these structural and functional parameters.

Results. Hemoglobin and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 DM individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 DM but had no effect in Hp 1-1 DM.

Conclusions. Vitamin E significantly improves the quality of HDL in Hp 2-2 DM individuals.