Haptoglobin Genotype Is a Regulator of Reverse Cholesterol Transport in Diabetes In Vitro and In Vivo

Asleh, Rabea; Miller-Lotan, Rachael; Aviram, Michael; Hayek, Tony; Yulish, Michael; Levy, Joanne E.; Miller, Benjamin; Blum, Shany; Milman, Uzi; Shapira, Chen; Levy, Andrew P.

doi:10.1161/01.res.0000251741.65179.56

Cited by 83 publications

(58 citation statements)

References 39 publications

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“…29 Moreover, we have shown that reverse cholesterol transport is impaired in Hp 2-2 DM mice. 30 Thirdly, we have demonstrated that the Hp 2 protein is an inferior antioxidant compared with the Hp 1 protein and that these differences are accentuated in DM. 16 -18 The antioxidant function of Hp is attributable to its ability to neutralize hemoglobin which is capable of generating the highly reactive hydroxyl radical.…”

Section: Discussionmentioning

confidence: 76%

Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Milman

Blum

Shapira

et al. 2008

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254

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Objective-Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM). The Hp gene is polymorphic with 2 common alleles, 1 and 2. The Hp 2 allelic protein product provides inferior antioxidant protection compared with the Hp 1 allelic product. We sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2-2 genotype, a subgroup that comprises 2% to 3% of the general population. Methods and Results-1434 DM individuals Ն55 years of age with the Hp 2-2 genotype were randomized to vitamin E (400 U/d) or placebo. The primary composite outcome was myocardial infarction, stroke, and cardiovascular death. At the first evaluation of events, 18 months after initiating the study, the primary outcome was significantly reduced in individuals receiving vitamin E (2.2%) compared with placebo (4.7%; Pϭ0.01) and led to early termination of the study. xtensive preclinical and observational studies showing the apparent benefit from vitamin E in preventing cardiovascular events created an atmosphere in which more than 40% of cardiologists were routinely prescribing high dose vitamin E. 1 Over the past 10 years, several prospective randomized clinical trials have investigated whether vitamin E supplementation provides cardiovascular protection. 2-9 The overwhelming consensus from these studies is that vitamin E supplementation does not provide cardiovascular benefit. 10 -11 To the contrary, meta-analysis of these studies suggests high dose vitamin E supplementation may increase mortality, 12 and several opinion articles have called for a moratorium on prescription of high dose vitamin E supplements. 10 -12 A possible explanation for why these studies failed in spite of solid preclinical data are the inadequate nature of patient selection in these studies. 13 High-dose antioxidant therapy may only provide benefit to individuals who suffer from particularly high levels of oxidative stress. Conclusions-VitaminThe haptoglobin (Hp) genotype may help identify patients with high levels of oxidative stress and who may benefit from antioxidant therapy with vitamin E. 14 The Hp gene is polymorphic with 2 common classes of alleles denoted 1 and 2. 15 We and others have demonstrated that the Hp 2 allele protein product is an inferior antioxidant compared with the Hp 1 allele protein product. 16 -20 These differences in antioxidant protection are profoundly accentuated in the diabetic state resulting in a marked relative increase in oxidative stress in Hp 2 transgenic mice and Hp 2-2 individuals with DM. 16 -20 The distribution of the 3 Hp genotypes in Western societies is approximately 16% Hp 1-1, 36% Hp 2-2, and 48% Hp 2-1. 15 We have demonstrated an interaction between the Hp genotype and DM on the development of cardi...

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Section: Discussionmentioning

confidence: 76%

Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Milman

Blum

Shapira

et al. 2008

ATVB

Self Cite

254

189

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“…114, 116 The prevalences of haptoglobin genotypes in the EDC T1DM cohort were 11.5%, 41.3%, and 47.2%, respectively. 117 In T1DM, there is an independent 2-fold increased incidence of CAD in haptoglobin 2-2 carriers compared with those with the haptoglobin 1-1 genotype 117 ; the 2-1 genotype is associated with an intermediate effect of increased CVD risk.…”

Section: Genetics and Atherosclerosis In T1dmmentioning

confidence: 99%

“…168,169 Additionally, as noted earlier, the less efficient handling of heme by the haptoglobin 2-2 genotype in patients with T1DM leaves these complexes less capable of being removed by macrophages, which allows them to associate with HDL, which renders it less functional. 116 Recent data from the EDC study suggest that the usual inverse association between HDL-C and CAD risk, although retained in men, is altered in women with T1DM, who show little increased protection with concentrations above the range of 50 to 60 mg/dL. 170 Conventionally, pharmacotherapy is used more aggressively for patients with T1DM and lipid disorders than for nondiabetic patients; however, recommendations for treatment are mostly extrapolated from interventional trials in adults with T2DM, in which rates of CVD events are equivalent to those in secondary prevention populations.…”

Section: Dyslipidemiamentioning

confidence: 99%

Type 1 Diabetes Mellitus and Cardiovascular Disease

Ferranti¹,

Boer²,

Fonseca³

et al. 2014

Circulation

293

122

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“…Cholesterol efflux. Serum from mice or humans treated with placebo or vitamin E was assessed for its ability to promote the efflux of [ 3 H]cholesterol from macrophages (26). Study drugs.…”

Section: Hdl-associated Lipid Peroxides and Hdl-associated Redox Actimentioning

confidence: 99%

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

et al. 2008

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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.

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Haptoglobin Genotype Is a Regulator of Reverse Cholesterol Transport in Diabetes In Vitro and In Vivo

Cited by 83 publications

References 39 publications

Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Type 1 Diabetes Mellitus and Cardiovascular Disease

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

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