Haptoglobin Phenotype Is Associated With High-Density Lipoprotein-Bound Hemoglobin Content and Coronary Endothelial Dysfunction in Patients With Mild Nonobstructive Coronary Artery Disease.

Objective- Coronary endothelial dysfunction (ED) is an early stage of atherosclerosis and is associated with impaired high-density lipoprotein (HDL) function. A functional polymorphism at the haptoglobin (Hp) gene locus (rs72294371) has been associated with marked differences in HDL structure and function. We sought to determine whether Hp phenotype was associated with coronary ED and whether the amount of hemoglobin (Hb) tethered to HDL via Hp was Hp-type dependent and associated with ED. Approach and Results- Microvascular and epicardial coronary endothelial function was assessed in 338 individuals with nonobstructive coronary artery disease. Microvascular ED was defined as <50% change in coronary blood flow and epicardial ED as ≥20% decrease in coronary artery diameter after intracoronary acetylcholine infusion. The amount of Hb bound to HDL was measured by ELISA after HDL purification from plasma samples using immune-affinity chromatography. One hundred and seventy of the individuals in this study (50.3%) were diagnosed with microvascular ED, 143 (42.3%) with epicardial ED, and 67 (19.7%) had diabetes mellitus (DM). Hp phenotype was significantly associated with microvascular ( P=0.01) and epicardial ED ( P=0.04) among DM individuals. There was a significant and inverse correlation between the amount of HDL-bound Hb and change in coronary blood flow (r=-0.40; P<0.0001) and in coronary artery diameter (r=-0.44; P<0.0001) in response to acetylcholine infusion. Hb content of HDL was significantly increased in individuals with Hp 2-2 and DM. In a logistic regression model, Hp 2-2 phenotype was associated with microvascular ED (odds ratio, 1.9; P=0.03) and the amount of HDL-bound Hb was an independent predictor of both microvascular (odds ratio, 4.6 for each 1-SD increase; P<0.0001) and epicardial (odds ratio, 2.2; P<0.0001) ED. Conclusions- Hp phenotype is significantly associated with coronary ED in DM individuals. This association is likely related to increased Hb tethering to HDL via Hp 2-2 in DM.

Haptoglobin Genotype Is a Determinant of Hemoglobin Adducts and Vitamin E Content in HDL.

Haptoglobin (Hp) is an abundant hemoglobin- (Hb-) binding serum protein and a constituent of the HDL proteome. In man, there exists a common polymorphism at the Hp locus with two common alleles defined by the presence (Hp 2 allele) or absence (Hp 1 allele) of a 1.7 kb in-frame partial duplication of exons 3 and 4 of the Hp gene. Numerous studies have demonstrated that the Hp 2-2 genotype is associated with a 3-5-fold increase in vascular disease among individuals with diabetes mellitus (DM). Increased Hp-Hb complex has been shown to be associated with the HDL of Hp 2-2 DM individuals. Hb-associated HDL has been proposed to result in the oxidation of HDL and the consumption of antioxidants in HDL, such as vitamin E, rendering the HDL further susceptible to oxidation. In this study, we set out to identify proteins which become cross-linked to Hb in HDL and to measure vitamin E in HDL as a function of the Hp genotype. We report on the identification of a novel 72 kd Hb reactive species which is cross-linked to HDL and demonstrate that vitamin E in HDL is decreased in Hp 2-2 DM individuals.

Patient selection and vitamin E treatment in diabetes mellitus.

In diabetes, there is an increase in oxidative stress due to elevated glucose levels in the plasma. High glucose promotes glycosylation, of both plasma and cellular proteins, which particularly affects the endothelial-cell lining of the blood vessel wall and interferes with its normal function. Thus, diabetes mellitus patients suffer from a higher incidence of cardiovascular complications such as atherosclerosis as compared with the nondiabetic population. Haptoglobin (Hp) is a plasma protein that binds free hemoglobin and prevents heme-iron mediated oxidation. There are three different types of Hp, which differ in their antioxidant ability. Several clinical studies have shown that the Hp 2-2 genotype is associated with higher incidence of cardiovascular diseases among diabetics. Vitamin E, a low-cost, easy-to-use antioxidant, was found to decrease the risk of developing cardiovascular diseases in Hp 2-2 diabetic patients. 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.

Haptoglobin genotype and its role in determining heme-iron mediated vascular disease.

Haptoglobin (Hp) is a hemoglobin (Hb) binding protein whose major function is to prevent heme-iron mediated oxidation. The polymorphic nature of the Hp gene results in varying levels of antioxidant function associated with the protein products. Multiple clinical studies have now determined that the Hp 2-2 genotype is associated with an increased risk of developing vascular complications in patients suffering from diabetes. The mechanism for this phenomenon is a decrease in antioxidant capability associated with the Hp 2-2 protein. Specifically, heme iron associated with the Hp2-2/Hb complex is more redox active than other Hp type complexes and has been shown in a number of systems to lead to increased levels of oxidative stress in the form of oxidized lipids and decreased lipoprotein function. In addition, Hp 2-2/Hb complexes are cleared less efficiently from the circulation, leading to a buildup of iron in the plasma and in tissues. Recent analyses from clinical studies utilizing vitamin E treatment have shown beneficial results specifically in the diabetic Hp 2-2 genotype population. 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.

Haptoglobin: basic and clinical aspects.

Haptoglobin is an abundant hemoglobin-binding protein present in the plasma. The function of haptoglobin is primarily to determine the fate of hemoglobin released from red blood cells after either intravascular or extravascular hemolysis. There are two common alleles at the Hp genetic locus denoted 1 and 2. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance. In particular, individuals with the Hp 2-2 genotype and diabetes mellitus appear to be at significantly higher risk of microvascular and macrovascular complications. A pharmacogenomic strategy of administering high dose antioxidants specifically to Hp 2-2 DM individuals may be clinically effective.