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.

Public Health Relevance

We have shown that the Haptoglobin 2-2 geneotype is associated with an increased incidence of cardiovascular events in individuals with Diabetes Mellitus. We have previously proposed that this may be mediated thru defective HDL function. In this project we will study the mechanism through which the Hp 2-2 genotype promotes HDL dysfunction and how antioxidative therapy can prevent and reverse this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
4R01DK085226-05
Application #
8516953
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Jones, Teresa L Z
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$128,193
Indirect Cost
$9,496
Name
Technion-Israel Institute of Technology
Department
Type
DUNS #
600133854
City
Haifa
State
Country
Israel
Zip Code
32000
Asleh, Rabea; Ward, John; Levy, Nina S et al. (2014) Haptoglobin genotype-dependent differences in macrophage lysosomal oxidative injury. J Biol Chem 289:16313-25
Vardi, Moshe; Levy, Nina S; Levy, Andrew P (2013) Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection. J Lipid Res 54:2307-14
Cahill, Leah E; Jensen, Majken K; Chasman, Daniel I et al. (2013) Currently available versions of genome-wide association studies cannot be used to query the common haptoglobin copy number variant. J Am Coll Cardiol 62:860-1
Cahill, Leah E; Levy, Andrew P; Chiuve, Stephanie E et al. (2013) Haptoglobin genotype is a consistent marker of coronary heart disease risk among individuals with elevated glycosylated hemoglobin. J Am Coll Cardiol 61:728-37
Levy, Nina S; Vardi, Moshe; Blum, Shany et al. (2013) An enzyme linked immunosorbent assay (ELISA) for the determination of the human haptoglobin phenotype. Clin Chem Lab Med 51:1615-22
Ravona-Springer, Ramit; Heymann, Anthony; Schmeidler, James et al. (2013) Haptoglobin 1-1 genotype is associated with poorer cognitive functioning in the elderly with type 2 diabetes. Diabetes Care 36:3139-45
Goldenstein, Hagit; Levy, Nina S; Lipener, Yisrael T et al. (2013) Patient selection and vitamin E treatment in diabetes mellitus. Expert Rev Cardiovasc Ther 11:319-26
Vardi, Moshe; Levy, Andrew P (2012) Is it time to screen for the haptoglobin genotype to assess the cardiovascular risk profile and vitamin E therapy responsiveness in patients with diabetes? Curr Diab Rep 12:274-9
Costacou, Tina; Levy, Andrew P (2012) Haptoglobin genotype and its role in diabetic cardiovascular disease. J Cardiovasc Transl Res 5:423-35
Farbstein, Dan; Levy, Andrew P (2012) HDL dysfunction in diabetes: causes and possible treatments. Expert Rev Cardiovasc Ther 10:353-61

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