The Haptoglobin 2-2 Phenotype Affects Serum Markers of Iron Status in Healthy Males

Abstract

Background: Human iron status is influenced by environmental and genetic factors. We hypothesized that the genetic polymorphism of haptoglobin (Hp), a hemoglobin-binding plasma protein, could affect iron status. Methods: Reference values of serum iron status markers were compared according to Hp phenotypes (Hp 1-1, Hp 2-1, Hp 2-2; determined by starch gel electrophoresis) in 717 healthy adults. Iron storage was investigated in peripheral blood monocyte-macrophages by measuring cytosolic L- and H-ferritins and by in vitro uptake of radiolabeled (125I) hemoglobin-haptoglobin complexes. Results: In males but not in females, the Hp 2-2 phenotype was associated with higher serum iron (P <0.05), transferrin saturation (P <0.05), and ferritin (P <0.01) concentrations than Hp 1-1 and 2-1, whereas soluble transferrin receptor concentrations were lower (P <0.05). Moreover, serum ferritin correlated with monocyte L-ferritin content (r = 0.699), which was also highest in the male Hp 2-2 subgroup (P <0.01). In vitro, monocyte-macrophages took up a small fraction of 125I-labeled hemoglobin complexed to Hp 2-2 but not to Hp 1-1 or 2-1. Conclusions: The Hp 2-2 phenotype affects serum iron status markers in healthy males and is associated with higher L-ferritin concentrations in monocyte-macrophages because of a yet undescribed iron delocalization pathway, selectively occurring in Hp 2-2 subjects.

Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis

“…In healthy men, Hp 2‐2 was found to be associated with macrophage iron accumulation when compared with men with Hp 1‐1 or Hp 1–2 (Langlois et al, 2000). Differences in turnover and haemoglobin binding may explain these changes in iron storage for Hp 2‐2.…”

“…Many studies implicate haptoglobin phenotype as a possible contributor towards the risk of developing a variety of diseases (Langlois & Delanghe, 1996). Furthermore, in healthy men, Hp 2‐2 was found to be associated with a higher transferrin saturation, lower transferrin receptor concentrations, and increased serum ferritin and macrophage ferritin concentrations when compared with men with Hp 1‐1 or Hp 2‐1 (Langlois et al, 2000). Haptoglobin has also been implicated as a factor modifying the phenotype in hereditary haemochromatosis as Hp 2‐2 was over‐represented in haemochromatosis patients homozygous for the C282Y mutation, and these patients had higher serum iron and ferritin concentrations than patients with Hp 2‐1 and 1‐1 (Van Vlierberghe et al, 2001).…”

Haptoglobin genotype, anaemia and malaria in Gambian children

“…Although there are some reports of differences in iron status by haptoglobin phenotype (Delanghe et al. 1998; Langlois et al. 2000), others have not observed any association (Kasvosve et al.…”

“…1997; Asleh et al. 2005), iron delocalisation within monocytes (Langlois et al. 2000) and immune regulation (Arredouani et al.…”

Donor haptoglobin phenotype determines outcome following liver transplantation

“…The Hp phenotype is a determinant factor in iron homeostasis. In male patients, the Hp 2‐2 phenotype is associated with a higher iron load [12], which has also been observed in pathological conditions such as hereditary hemochromatosis [13] and human immunodeficiency virus (HIV) infection [14]. Complexes of Hb and multimeric Hp 2‐2 exhibit a higher affinity for CD163 than Hb–Hp 1‐1 complexes, which may explain an increased iron accumulation in this phenotype [15].…”