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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Jones, Teresa L Z
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Technion-Israel Institute of Technology
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Asleh, Rabea; Levy, Nina S; Doros, Gheorge et al. (2016) Haptoglobin Genotype as a Determinant of Benefit or Harm From Niacin for Participants With Diabetes. J Am Coll Cardiol 67:2553-4
Orchard, Trevor J; Backlund, Jye-Yu C; Costacou, Tina et al. (2016) Haptoglobin 2-2 genotype and the risk of coronary artery disease in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). J Diabetes Complications 30:1577-1584
Cahill, Leah E; Jensen, Majken K; Chiuve, Stephanie E et al. (2015) The Risk of Coronary Heart Disease Associated With Glycosylated Hemoglobin of 6.5% or Greater Is Pronounced in the Haptoglobin 2-2 Genotype. J Am Coll Cardiol 66:1791-1799
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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
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
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
Orchard, Trevor J; Sun, Wanjie; Cleary, Patricia A et al. (2013) Haptoglobin genotype and the rate of renal function decline in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes 62:3218-23
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
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

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