Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype

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.

Genotype-Dependent Impairment of Hemoglobin Clearance Increases Oxidative and Inflammatory Response in Human Diabetic Atherosclerosis

“…MPO has been associated with increased risk of coronary heart disease [32][33][34] and dysfunctional high-density lipoprotein, also seen with Hp2-2 diabetic patients. 35 This study also documented significant downregulation of anti-inflammatory mediator IL-10 gene and protein, an important molecule in the resolution of inflammation. 36,37 Lower serum IL-10 levels are linked to acute coronary syndromes increasing future atherothrombotic events.…”

“…Hp2-2 genotype may also play a role in high-density lipoprotein function, reducing cholesterol efflux, as previously reported. 35 Finally, the clinical relevance of Hp2-2 genotype in other vascular territories different from peripheral vascular disease is supported by increases in coronary calcification, 39 myocardial infarction, 40 congestive heart failure, and cardiac death. 41 Our results extend these observations by suggesting a potential role for Hp2-2 genotype in the modulation of lower extremity atherosclerosis in the setting of DM.…”

The effects of omega-3 plus vitamin E and zinc plus vitamin C supplementation on cardiovascular risk markers in postmenopausal women with type 2 diabetes

“…In contrast, vitamin C supplementation increased the oxidative activity of Hb 2-2-hemoglobin bound to HDL and not only increased HDL oxidation but also resulted in a proinflammatory and proatherogenic status [Asleh et al 2008]. …”

Divergent Effects ofα-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

“…These differences in the antioxidant activity of the Hp 1 and Hp 2 proteins against Hb are dramatically exaggerated when Hb is glycosylated (1), as occurs to a greater extent in DM. Furthermore, despite the greater urgency of clearing the Hp 2-Hb complex in DM due to its increased redox activity, the clearance of the Hp 2-Hb complex by the CD163 receptor is impaired in DM, resulting in a further amplification of oxidative injury that may be mediated by Hb in Hp 2-2 DM individuals (3). We have recently demonstrated that an important target for Hp 2-Hb-mediated oxidation in DM is the high density lipoprotein (HDL) particle.…”