In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease.
Hemoglobin (Hb) released during hemolysis is a potent oxidant. Extracorpuscular Hb may enter the vessel wall and mediate low-density lipoprotein oxidation, thereby promoting the development and progression of atherosclerosis. Haptoglobin (Hp) is an antioxidant protein as a result of its ability to bind Hb and block Hb-induced oxidative damage. Hp also facilitates the removal of Hb from the extravascular compartment via the CD163 macrophage scavenger receptor. In man, there are two common alleles for Hp denoted 1 and 2, and correspondingly, three different possible genotypes: Hp1-1, Hp2-1, and Hp2-2. We have recently demonstrated in several longitudinal studies that Hp genotype is an independent risk factor for diabetic vascular complications. Specifically, we have shown that diabetic individuals with Hp2-2 are more likely to develop nephropathy, retinopathy, and cardiovascular disease as compared with those with Hp2-1 or Hp1-1. Mechanistically, we have found significant Hp type differences in the antioxidant and CD163-mediated scavenging and activation functions of the different Hp protein types. Furthermore, we have demonstrated that these functions are modified in the diabetic state. In this review, we focus on the clinical studies associating the Hp polymorphism and diabetic vascular complications, and the molecular basis behind this interaction.
Asleh
Rabea
R
Faculty of Medicine,Technion-Israel Institute of Technology, Haifa, Israel.
Levy
Andrew P
AP
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000975:Antioxidants / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D023903:Coronary Restenosis / Q000235:genetics; D003925:Diabetic Angiopathies / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics; D003930:Diabetic Retinopathy / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008958:Models, Molecular; D016017:Odds Ratio; D018384:Oxidative Stress; D018579:Patient Selection; D010641:Phenotype; D011110:Polymorphism, Genetic; D020836:Protein Structure, Quaternary; D011956:Receptors, Cell Surface / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000975:Antioxidants; D000098902:CD163 Antigen; C485359:HP protein, human; D006242:Haptoglobins; D006454:Hemoglobins; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; C035492:haptoglobin-hemoglobin complex; C099252:oxidized low density lipoprotein