Vitamin E therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2-1 genotype

Abstract

Objective Vitamin E provides cardiovascular protection to individuals with Diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with Diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. Research design and methods Fifty-nine individuals with Diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400 IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. Results Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. Conclusion There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function. (clinicaltrials.gov NCT01113671).

Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial

“…Prospective type 2 diabetes investigations have reported increased cardiovascular risk with Hp 2-2 [10–13] and improvements in HDL function with α-tocopherol in Hp 2-2 (but not Hp 1-1) carriers [8–9], suggesting that vitamin E may modify the Hp 2-2 associated cardiovascular risk. Retrospective analyses of the HOPE trial demonstrated that α-tocopherol supplementation in type 2 diabetes with Hp 2-2 reduces myocardial infarction and cardiovascular mortality [14].…”

Pharmacogenomic interaction between the Haptoglobin genotype and vitamin E on atherosclerotic plaque progression and stability

“…For example, the Hp 2-2 protein can bind directly to helix 6 of apoA1 on HDL and thereby tether Hb to HDL resulting in the oxidation of HDL [28]. In vivo, both in Hp transgenic mice and in man, the Hp 2-2 genotype has been associated with increased oxidation of HDL and depressed HDL function [28,36,37]. In addition the Hp 1-1-Hb and Hp 2-2-Hb complexes are recognized and processed differently by macrophages, resulting in increased redox active iron load (both in the plaque and tethered to HDL) in Hp 2-2 [22,23,29].…”

“…Second, we have demonstrated a pharmacogenomic interaction between the Hp genotype and vitamin E on HDL function in man (and in mice). In three independent studies in man vitamin E has been shown to prevent HDL oxidation and thereby improve HDL function in Hp 2-2 DM but not in non Hp 2-2 DM [28,36,37]. The ability of vitamin E to prevent HDL oxidation and improve HDL function in Hp 2-2 DM may be related to a relative vitamin E deficiency in Hp 2-2 HDL.…”

Dietary Antioxidant and Oxidative Stress: Interaction between Vitamins and Genetics

“…Controlled studies of the effects of α-tocopherol supplementation on cardiovascular risk factors studies have reported beneficial effects of supplementation, but limited to individuals who had a particular genotype of haptoglobin (Hp2-2). Among male smokers supplemented with α-tocopherol (50 mg / day) for 3 years, polymorphisms (rs964184, rs2108622, rs7834588) were identified in three different loci (11q23.3, 8q12.3 and 19pter-p13.11) that, associated, accounted for 3.4% of the residual variation in serum vitamin E levels during supplementation [30]. For the future, it is expected that the supplements and food intake may be adequate based on the individual's genotype.…”