Oxidation Hypothesis Revisited: Haptoglobin Genotype &Diabetic Atherosclerosis

Summary

Principal Investigator: ANDREW PETER LEVY
Abstract: Project Abstract Acute ischemic syndromes due to a higher incidence of plaque rupture and thrombosis are common complications associated with Diabetes Mellitus (DM). The oxidative modification hypothesis of atherosclerosis predicts that oxidative events in the vessel wall are responsible for the initiation and progression of atherosclerotic lesions. As DM represents a state of heightened oxidative stress, the accelerated atherosclerosis and increased atherothrombosis in DM are thought to be due to increased oxidative modifications. Paradoxically, anti-oxidant strategies to reduce cardiovascular events from atherosclerosis in DM have failed, possibly due to the inadequate nature of patient selection. High dose antioxidant therapy may only provide benefit to individuals with particularly high levels of oxidative stress. We have shown, in vitro and in vivo, that the 2 allele of the Haptoglobin (Hp) gene is associated with high levels of oxidative stress in DM. In clinical studies we have found that DM individuals with the Hp 2-2 genotype have as much as a 500% increase in cardiovascular events as compared to Hp 1-1 DM individuals. Based on this association of the Hp genotype and oxidative stress we have suggested a pharmacogenomic approach for identifying individuals who will benefit from antioxidant therapy. We have recently prospectively tested this approach in a double-blind placebo controlled trial and found that antioxidant therapy with vitamin E significantly reduced atherothrombosis in Hp 2-2 DM individuals. We hypothesize that the Hp 2-2 genotype interacts with DM to promote HDL oxidative modification and dysfunction as a result of the direct association of the Hp 2-2-Hb complex with HDL. To test our hypothesis we have designed both mechanistic and interventional studies using a unique mouse model expressing the Hp 2 protein and human banked serum from ICARE and two prospective interventional studies.. The specific aims are to assess the relationship between the Hp genotype and HDL structure and function in DM (SA#1);to determine how the Hp-Hb complex associates with HDL and whether blocking this association can decrease HDL oxidation and improve HDL function (SA#2);and to demonstrate that HDL function can be improved in Hp 2-2 DM by antioxidants (SA#3). Results from this study will shed light on the mechanistic correlation between the Hp genotype and cardiovascular diseases associated with DM, thus promoting application of a pharmacogenomic approach to identifying patients who will benefit from antioxidative treatment.
Funding Period: 2009-09-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype
    Rabea Asleh
    Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
    Antioxid Redox Signal 12:209-17. 2010
  2. pmc Haptoglobin genotype and its role in diabetic cardiovascular disease
    Tina Costacou
    Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
    J Cardiovasc Transl Res 5:423-35. 2012
  3. pmc Haptoglobin genotype and its role in determining heme-iron mediated vascular disease
    Hagit Goldenstein
    The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron Street, Bat Galim P O B 9649, Haifa 31096, Israel
    Pharmacol Res 66:1-6. 2012
  4. pmc Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus
    Rabea Asleh
    Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron St Bat Galim, POB 9649, Haifa, Israel
    Free Radic Biol Med 53:779-86. 2012
  5. pmc Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus - natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature
    Moshe Vardi
    Department of Medicine, Carmel Medical Center, Haifa, Israel
    Eur J Intern Med 23:628-32. 2012
  6. pmc Haptoglobin genotype is a consistent marker of coronary heart disease risk among individuals with elevated glycosylated hemoglobin
    Leah E Cahill
    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
    J Am Coll Cardiol 61:728-37. 2013
  7. pmc Patient selection and vitamin E treatment in diabetes mellitus
    Hagit Goldenstein
    The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron Street, Bat Galim PO 9649, Haifa, 31096, Israel
    Expert Rev Cardiovasc Ther 11:319-26. 2013
  8. pmc An enzyme linked immunosorbent assay (ELISA) for the determination of the human haptoglobin phenotype
    Nina S Levy
    Technion Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
    Clin Chem Lab Med 51:1615-22. 2013
  9. pmc Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection
    Moshe Vardi
    Harvard Clinical Research Institute, Boston, MA, USA
    J Lipid Res 54:2307-14. 2013
  10. pmc Haptoglobin genotype and the rate of renal function decline in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study
    Trevor J Orchard
    Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 62:3218-23. 2013

Detail Information

Publications24

  1. pmc Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype
    Rabea Asleh
    Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
    Antioxid Redox Signal 12:209-17. 2010
    ..Choosing the correct antioxidant in the correct subset of patients may be critical in order to demonstrate benefit from antioxidant therapy...
  2. pmc Haptoglobin genotype and its role in diabetic cardiovascular disease
    Tina Costacou
    Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
    J Cardiovasc Transl Res 5:423-35. 2012
    ..This manuscript presents an overview of the biology of the haptoglobin genotype and reviews the literature concerning its role in the development of cardiovascular disease among individuals with diabetes mellitus...
  3. pmc Haptoglobin genotype and its role in determining heme-iron mediated vascular disease
    Hagit Goldenstein
    The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron Street, Bat Galim P O B 9649, Haifa 31096, Israel
    Pharmacol Res 66:1-6. 2012
    ..The use of vitamin E in the treatment of Hp 2-2 diabetics has the potential to greatly reduce medical costs and improve quality of life in the ever-growing diabetic population...
  4. pmc Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus
    Rabea Asleh
    Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron St Bat Galim, POB 9649, Haifa, Israel
    Free Radic Biol Med 53:779-86. 2012
    ..Iron-induced renal tubular injury may play a major role in the development of diabetic nephropathy and may be a target for slowing the progression of renal disease...
  5. pmc Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus - natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature
    Moshe Vardi
    Department of Medicine, Carmel Medical Center, Haifa, Israel
    Eur J Intern Med 23:628-32. 2012
    ..We aim to summarize the evidence about cardiovascular risk in diabetic patients, according to their Hp type, and the effect of vitamin E treatment on these sub-groups...
  6. pmc Haptoglobin genotype is a consistent marker of coronary heart disease risk among individuals with elevated glycosylated hemoglobin
    Leah E Cahill
    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
    J Am Coll Cardiol 61:728-37. 2013
    ..This study sought to investigate into the biologically plausible interaction between the common haptoglobin (Hp) polymorphism rs#72294371 and glycosylated hemoglobin (HbA(1c)) on risk of coronary heart disease (CHD)...
  7. pmc Patient selection and vitamin E treatment in diabetes mellitus
    Hagit Goldenstein
    The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron Street, Bat Galim PO 9649, Haifa, 31096, Israel
    Expert Rev Cardiovasc Ther 11:319-26. 2013
    ..This review summarizes several studies that show the importance of vitamin E supplementation in a specific subgroup of patients, diabetic individuals carrying the Hp 2-2 genotype...
  8. pmc An enzyme linked immunosorbent assay (ELISA) for the determination of the human haptoglobin phenotype
    Nina S Levy
    Technion Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
    Clin Chem Lab Med 51:1615-22. 2013
    ..We sought to develop a rapid and accurate test for Hp phenotype (which is 100% concordant with the three major Hp genotypes) to facilitate widespread diagnostic testing as well as prospective clinical trials...
  9. pmc Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection
    Moshe Vardi
    Harvard Clinical Research Institute, Boston, MA, USA
    J Lipid Res 54:2307-14. 2013
    ..This review details the scientific basis and clinical evidence related to the effect of vitamin E on CV outcomes, and the importance of proper patient selection in gaining therapeutic benefit from this intervention. ..
  10. pmc Haptoglobin genotype and the rate of renal function decline in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study
    Trevor J Orchard
    Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 62:3218-23. 2013
    ..We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study. ..
  11. pmc Is it time to screen for the haptoglobin genotype to assess the cardiovascular risk profile and vitamin E therapy responsiveness in patients with diabetes?
    Moshe Vardi
    Harvard Clinical Research Institute, 930 Commonwealth Avenue, Boston, MA 02467, USA
    Curr Diab Rep 12:274-9. 2012
    ....
  12. pmc HDL dysfunction in diabetes: causes and possible treatments
    Dan Farbstein
    Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
    Expert Rev Cardiovasc Ther 10:353-61. 2012
    ..This review will summarize the changes that occur in HDL in diabetes mellitus and how these changes lead to HDL dysfunction. Possible treatments for HDL dysfunction are also briefly described...
  13. pmc Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype
    Shany Blum
    Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
    Pharmacogenomics 11:675-84. 2010
    ..As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals...
  14. pmc The genetics of vascular complications in diabetes mellitus
    Dan Farbstein
    Technion Israel Institute of Technology, Haifa, Israel
    Cardiol Clin 28:477-96. 2010
    ..Use of the knowledge of these genetic differences among individuals in targeting drug therapy (pharmacogenomics) is also discussed...
  15. pmc Antioxidant vitamins and their use in preventing cardiovascular disease
    Dan Farbstein
    Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
    Molecules 15:8098-110. 2010
    ..We provide one example of how pharmacogenomics may be used to identify a sub-population which may indeed benefit from antioxidant supplementation...
  16. pmc Genetics of redox systems and their relationship with cardiovascular disease
    Dan Farbstein
    The Ruth and Bruce Faculty of Medicine, Technion Israel Institute of Technology, Efron St, POB 9649, Haifa 31096, Israel
    Curr Atheroscler Rep 13:215-24. 2011
    ..Reports regarding pharmacogenetic implications of these polymorphisms, where such exist, are discussed as well...
  17. pmc Vitamin E therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2-1 genotype
    Dan Farbstein
    Department of Anatomy and Cell Biology, Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
    Atherosclerosis 219:240-4. 2011
    ..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...
  18. pmc Haptoglobin genotype predicts development of coronary artery calcification in a prospective cohort of patients with type 1 diabetes
    Melissa Simpson
    Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA
    Cardiovasc Diabetol 10:99. 2011
    ..We hypothesized that the Hp genotype would predict progression of coronary artery calcification (CAC), a marker of subclinical atherosclerosis...
  19. pmc Haptoglobin 1-1 genotype is associated with poorer cognitive functioning in the elderly with type 2 diabetes
    Ramit Ravona-Springer
    Corresponding author Ramit Ravona Springer
    Diabetes Care 36:3139-45. 2013
    ..This study investigated whether Hp genotype is associated with cognitive function in cognitively normal elderly diabetic subjects...

Research Grants30

  1. Novel mechanisms of niacin to improve HDL function: Role of myeloperoxidase
    Moti L Kashyap; Fiscal Year: 2013
    ..3. Define cellular mechanism of action of niacin on: MPO-mediated oxidative modification of HDL- apoAI, formation of "dysfunctional HDL", and improvement in HDL's anti-atherogenic properties. ..
  2. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  3. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  4. Biophysics of HDL Dysfunction
    Mary G Sorci-Thomas; Fiscal Year: 2013
    ..Development of these novel assays will make it possible, for the first time, to perform large clinical studies to fully test the idea that dysfunctional HDL is better indicator of atherosclerotic risk. ..
  5. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  6. Mechanisms for Dysfunctional HDL Formation in Familial Hypercholesterolemia
    Macrae F Linton; Fiscal Year: 2013
    ..Our results may lead to the development of new markers of HDL function, provide new pharmacologic targets for improving HDL function, and identify HDL as a target of therapy in FH patients. ..
  7. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  8. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
    ..The projects are highly interactive, and all three take full advantage of the proposed cores. ..
  9. Quantitative Assessment of HDL Function
    Jay W Heinecke; Fiscal Year: 2013
    ..The availability of these valuable resources will enable us to investigate specific mechanisms for generating dysfunctional HDL in subjects with CVD, the leading cause of death in industrialized societies. ..
  10. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  11. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  12. BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCES
    Bruce D Hammock; Fiscal Year: 2013
    ..abstract_text> ..
  13. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  14. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  15. Dissection of HDL function using mouse models
    Aldons Jake Lusis; Fiscal Year: 2013
    ..To validate candidate genes and pathways, we will employ a variety of in vitro and in vivo approaches, including cultured hepatocytes, transgenic mice, and gene targeted mice. ..
  16. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  17. HDL Function as a Biomarker for Atherosclerotic Risk in Rheumatoid Arthritis
    Christina Charles-Schoeman; Fiscal Year: 2013
    ..End of Abstract) ..
  18. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  19. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..