Abstract 10078: Pharmacogenomic Interaction Between the Hp Genotype and Vitamin E on Hdl Structure and Function
Introduction: Clinical trials have failed to demonstrate cardioprotection by vitamin E when provided indiscriminately to all individuals. We recently demonstrated that vitamin E significantly reduced incident CVD in individuals with Diabetes Mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype (36% of DM individuals). We have proposed and provided proof of concept experiments in transgenic mice and in humans that the beneficial affect of vitamin E in Hp 2-2 DM is mediated by its ability to prevent oxidative modification of HDL arising from the binding of redox active Hp 2-2-hemoglobin complex to a region of ApoA1 overlapping with the LCAT binding site. As opposed to Hp 2-2 DM individuals, Hp 2-1 DM individuals (50% of DM individuals) appear to have an increase in CV events when supplemented with vitamin E. The reason why vitamin E appears to be harmful in Hp 2-1 DM is not understood.
Hypothesis: We sought to test the hypothesis that there exists a pharmacogenomic interaction between the Hp genotype and vitamin E on HDL structure and function in individuals with DM.
Methods: We studied the effects of 400mg daily of vitamin E vs. placebo on HDL structure and function in individuals with Type II DM in a cross-over study. HDL function was assessed by its ability to promote cholesterol efflux from macrophages. The structure of HDL purified by affinity chromatography was assessed for lipid peroxides, complement, LCAT and nitration of apoA1. We also assessed the ability of recombinant LCAT to bind to these affinity purified HDLs.
Results: At baseline, the function of Hp 2-2 HDL was significantly impaired with marked lipid peroxidation and tyrosine nitration coupled with dramatic quantitative alterations of its protein cargo. LCAT protein was decreased by nearly 50% in Hp 2-2 DM HDL. Furthermore, the ability of purified LCAT to bind to Hp 2-2 DM HDL was significantly impaired. Compared to placebo, vitamin E appeared to improve these parameters of HDL structure and function in Hp 2-2 DM individuals but paradoxically resulted in a deterioration in Hp 2-1 DM individuals.
Conclusions: The benefit or harm of vitamin E supplementation in individuals with DM may be dependent on the Hp genotype.
- © 2010 by American Heart Association, Inc.