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Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

B cells play a role in atherosclerosis. B lymphocytes may reduce the progression of vascular disease. Antibody production against modified auto-antigens is an element in the atheroprotective involvement of B lymphocytes. Paradoxical evidence is emerging from animal studies that suggest a proatherogenic B-cell behaviour independently of autoantibody production. One aspect that has received limited consideration is the role of genetic susceptibility modulated by extracellular matrix proteins. Haptoglobin is a polymorphic glycoprotein that binds to CD22 on B lymphocytes. Hp phenotypes show an important molecular heterogeneity. Hp 2-2 has been linked to an increased susceptibility for atherosclerosis. Haptoglobin and its polymorphism play a role in B-cell migration and function. Hp phenotypes may influence B-T cell dialogue and T cell activation. Haptoglobin is involved in the interplay of lymphocytes, neutrophils, and monocytes. Haptoglobin binds to the CD11b/CD18 receptor and to mast cells. HDL particles can become pro-inflammatory through interactions of Hp-Hb complexes with apolipoprotein A1. Haptoglobin is a chemoattractant to pre-B lymphocytes and monocytes. Beyond the conventional view of haptoglobin as a marker of hemolysis, several findings point towards an immunomodulatory effect of haptoglobin in B-cell mediated progression of atherosclerosis. The balance between proatherogenic and protective immunological properties of the different Hp phenotypes determines if lesions progress or regress. Clinical studies indicate a strong association between the Hp 2-2 phenotype and a more frequent onset of diabetic complications and cardiovascular disease. Findings in animal models (where no haptoglobin polymorphism is present) cannot always be extrapolated to humans., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Ascorbic acid (vitamin C) is prone to oxidation in vivo. The human plasma protein haptoglobin (Hp) shows a genetic polymorphism with 3 major phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2) that show important functional differences. Despite an adequate nutritional supply, in Hp 2-2 individuals (most common among Asian populations) vitamin C is markedly lower in concentration and particularly prone to oxidation in vivo. Therefore, susceptibility to subclinical and clinical vitamin C deficiency (scurvy) is partly genetically determined. The genetic advantage of the Hp1 allele as a vitamin C stabilizing factor helps to elucidate the direction and successes of long-distance sea crossing human migrations in history. Clinical trials demonstrated Hp phenotype-related effects of antioxidant treatment. Because vitamin C is a first line antioxidant, Hp polymorphism and its effects on vitamin C have major clinical consequences; a marked difference in genetic susceptibility toward atherosclerosis between Hp phenotypes is attributable to variation in LDL oxidation. The classical view of vitamin C and scurvy being a pure nutritional condition needs to be updated. These findings should foster research investigating the role of Hp polymorphism in human disease, and in vitamin C deficiency and atherosclerosis in particular.

Background: Haptoglobin (Hp) polymorphism has been associated with blood pressure regulation and essential hypertension. We investigated Hp polymorphism in patients with preeclampsia., Methods: A total of 60 Caucasian women with preeclampsia were prospectively followed from hospital admission until delivery. Serum Hp phenotypes 1-1, 2-1, and 2-2 were determined by starch gel electrophoresis and compared with those in 200 normotensive controls of the same geographic and ethnic origin. Blood pressure and laboratory markers (serum uric acid, alanine aminotransferase, aspartate aminotransferase, platelet count, and 24-h proteinuria) were compared according to Hp phenotypes of preeclamptic women., Results: We found a higher Hp1 allele frequency in the preeclamptic group than in normotensive controls (0.517 vs. 0.400, p<0.05). The Hp 1-1 phenotype was present in 28% of preeclamptic patients vs. 16% of the controls, with an odds ratio (95% CI) of 2.08 (1.05-4.08) for Hp 1-1 vs. the other Hp phenotypes. Diastolic (p<0.005) and systolic (p<0.05) blood pressure and proteinuria (p<0.05) were highest in Hp 1-1 patients. Other laboratory markers were not significantly different between Hp phenotype subgroups., Conclusions: The Hp1 allele frequency was higher among preeclamptic patients and the Hp 1-1 phenotype was associated with more severe hypertension and proteinuria.

In humans the iron status is influenced by environmental and genetic factors. Among them, the genetic polymorphism of the hemoglobin (Hb)-binding plasma protein haptoglobin (Hp) has been shown to affect iron turnover. The best known biological function of Hp is capture of free Hb in plasma to allow hepatic recycling of heme iron and to prevent kidney damage during hemolysis. In healthy males, but not in females, the Hp 2-2 phenotype is associated with higher serum iron, higher transferrin saturation, and higher ferritin than Hp 1-1 and 2-1. Moreover, serum ferritin correlates with monocyte L-ferritin content, which is also highest in Hp 2-2 subjects due to endocytosis of multimeric Hb-Hp 2-2 complexes by the recently identified Hb scavenger receptor CD163 in macrophages. This iron delocalization pathway, occurring selectively in Hp 2-2 subjects, has important biological and clinical consequences. The Hp polymorphism is related to the prevalence and the outcome of various pathological conditions with altered iron metabolism such as hemochromatosis, infections, and atherosclerotic vascular disease.

The article reports on haptoglobin polymorphism and serum ferritin concentration in ageing subjects. In randomly selected control subjects, in blood donors homozygous for the HFE C282Y mutation, and in first-time blood donors lacking the HFE mutations, it was found that their was no influence of Hp type on transferrin saturation and serum ferritin concentration. It was found that the influence of Hp type on serum iron status was exclusively present in males aged 18-50 years. The influence of Hp 2-2 type on serum ferritin concentrations cannot be observed in subjects aged >50 years.