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The haptoglobin 2–2 genotype is associated with increased redox active hemoglobin derived iron in the atherosclerotic plaque

      In man the haptoglobin (Hp) gene is polymorphic with two common alleles denoted 1 and 2 [
      • Bowman B.H.
      • Kurosky A.
      Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation.
      ]. We have recently demonstrated in multiple independent longitudinal studies that there is an up to 500% increase in the incidence of cardiovascular disease in individuals with the Hp 2–2 genotype and diabetes mellitus (DM) [
      • Levy A.P.
      • Hochberg I.
      • Jablonski K.
      • et al.
      Haptoglobin phenotype and the risk of cardiovascular disease in individuals with diabetes: the strong heart study.
      ,
      • Roguin A.
      • Koch W.
      • Kastrati A.
      • et al.
      Haptoglobin genotype is predictive of major adverse cardiac events in the one year period after PTCA in individuals with diabetes.
      ,
      • Suleiman M.
      • Aronson D.
      • Asleh R.
      • et al.
      Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction.
      ,
      • Milman U.
      • Blum S.
      • Shapira C.
      • et al.
      Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2–2 genotype: a prospective, double-blinded clinical trial.
      ,
      • Costacou T.
      • Ferrell R.E.
      • Orchard T.J.
      Haptoglobin genotype: a determinant of cardiovascular complication risk in type I diabetes.
      ]. The normal function of Hp is to bind extracorpuscular hemoglobin (Hb) and promote its clearance after it is released into either the blood secondary to red cell intravascular hemolysis (6 g per day in a normal man) or into the extravascular compartment after hemorrhage (i.e., after hemorrhage into the atherosclerotic plaque) [
      • Bowman B.H.
      • Kurosky A.
      Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation.
      ]. We and others have previously demonstrated that the Hp 1 allele protein product is superior to the Hp 2 allele protein product in blocking Hb induced oxidation of multiple substrates including LDL and HDL [
      • Bamm V.V.
      • Tsemakhovich V.A.
      • Shaklai M.
      • Shaklai N.
      Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.
      ,
      • Frank M.
      • Lache O.
      • Enav B.
      • et al.
      Structure/function analysis of the anti-oxidant properties of haptoglobin.
      ,
      • Asleh R.
      • Miller-Lotan R.
      • Aviram M.
      • et al.
      Haptoglobin genotype is a regulator of reverse cholesterol transport in diabetes in vitro and in vivo.
      ]. The major pathway for clearance of the Hp–Hb complex from the blood as well as from the atherosclerotic plaque is via the monocyte/macrophage CD163 receptor [
      • Kristiansen M.
      • Graversen J.H.
      • Jacobsen C.
      • et al.
      Identification of the hemoglobin scavenger receptor.
      ]. We have demonstrated that the Hp 1–Hb complex is cleared more rapidly by the CD163 receptor than the Hp 2–Hb complex [
      • Asleh R.
      • Marsh S.
      • Shiltruck M.
      • et al.
      Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease.
      ]. Furthermore, the amount of the CD163 receptor expressed on monocyte/macrophages is decreased in Hp 2–2 and DM individuals [
      • Levy A.P.
      • Purosothaman K.R.
      • Levy N.S.
      • et al.
      Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2–2 genotype: implications for the response to intraplaque hemorrhage and plaque vulnerability.
      ]. In this study we set out to test the hypothesis that the Hp genotype regulates the turnover and oxidative activity of Hb in the atherosclerotic plaque.
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