Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.
Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.
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作者：
Asleh R;Blum S;Kalet-Litman S;Alshiek J;Miller-Lotan R;Asaf R;Rock W;Aviram M;Milman U;Shapira C;Abassi Z;Levy AP
目的-药物基因组学是个体化用药的关键组成部分。以色列的维生素E减少心血管事件研究是一项前瞻性的安慰剂对照研究，最近证明维生素E可以显著减少糖尿病患者和结合珠蛋白(HP)2-2基因(40%的糖尿病患者)的心血管疾病。然而，由于大量临床试验未能证明维生素E的益处，加上缺乏机制解释为什么维生素E只对Hp 2-2基因型的糖尿病患者有益，因此人们对这种药物基因组学范式的热情有限。在这项研究中，我们试图基于HP2-2基因和糖尿病相互作用促进高密度脂蛋白氧化修饰和功能障碍的假设，提供这样一个机制解释。研究设计和方法-从糖尿病患者或Hp1-1或Hp2-2基因型鼠分离的高密度脂蛋白中评估Hb和过氧化脂质。根据其促进巨噬细胞胆固醇外流的能力来评估高密度脂蛋白的功能。在Hp 2-2糖尿病人和Hp 1-1和Hp 2-2糖尿病小鼠中进行的交叉安慰剂对照研究评估了维生素E有利地改变这些结构和功能参数的能力。结果：HP2-2糖尿病患者和小鼠的Hb和与高密度脂蛋白相关的过氧化脂质升高，高密度脂蛋白功能受损。维生素E减少HP2-2糖尿病患者的高密度脂蛋白氧化修饰，改善高密度脂蛋白功能，但对HP1-1糖尿病患者无影响。结论：维生素E显著改善HP2-2糖尿病患者的高密度脂蛋白质量。
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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DOI：
10.1161/01.atv.0000251020.24399.a2
发表时间：
2007-01-01
影响因子：
8.7
作者：
Levy, Andrew P.;Levy, Joanne E.;Moreno, Pedro R.
通讯作者：
Moreno, Pedro R.
影响因子：
3.4
作者：
Rezaee, F;Casetta, B;Meijers, JCM
通讯作者：
Meijers, JCM
影响因子：
7.7
作者：
Costacou, Tina;Ferrell, Robert E.;Orchard, Trevor J.
通讯作者：
Orchard, Trevor J.
影响因子：
2.9
作者：
KUNITAKE, ST;CARILLI, CT;KANE, JP
通讯作者：
KANE, JP
影响因子：
20.1
作者：
Levy, Andrew P.;Purushothaman, K. Raman;Moreno, Pedro R.
通讯作者：
Moreno, Pedro R.