Polymorphism of human haptoglobin and its clinical importance

Abstract

Haptoglobin (Hp) is a plasma glycoprotein, the main biological function of which is to bind free hemoglobin (Hb) and prevent the loss of iron and subsequent kidney damage following intravascular hemolysis. Haptoglobin is also a positive acute-phase protein with immunomodulatory properties. In humans, the HP locus is polymorphic, with two codominant alleles (HP1 and HP2) that yield three distinct genotypes/phenotypes (Hp1-1, Hp2-1 and Hp2-2). The corresponding proteins have structural and functional differences that may influence the susceptibility and/or outcome in several diseases. This article summarizes the available data on the structure and functions of Hp and the possible effects of Hp polymorphism in a number of important human disorders.

haptoglobin; hemoglobin; genetic polymorphisms


REVIEW ARTICLE

Polymorphism of human haptoglobin and its clinical importance

Vânia Peretti de Albuquerque Wobeto; Tânia Regina Zaccariotto; Maria de Fátima Sonati

Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil

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ABSTRACT

Haptoglobin (Hp) is a plasma glycoprotein, the main biological function of which is to bind free hemoglobin (Hb) and prevent the loss of iron and subsequent kidney damage following intravascular hemolysis. Haptoglobin is also a positive acute-phase protein with immunomodulatory properties. In humans, the HP locus is polymorphic, with two codominant alleles (HP1 and HP2) that yield three distinct genotypes/phenotypes (Hp1-1, Hp2-1 and Hp2-2). The corresponding proteins have structural and functional differences that may influence the susceptibility and/or outcome in several diseases. This article summarizes the available data on the structure and functions of Hp and the possible effects of Hp polymorphism in a number of important human disorders.

Key words: haptoglobin, hemoglobin, genetic polymorphisms.

Human Haptoglobin

Haptoglobin, first described by Polonovski and Jayle (1938), is an α2-sialoglycoprotein synthesized mainly in hepatocytes in response to the secretion of cytokines such as interleukin (IL)-6, IL-1 and tumour necrosis factor (TNF) (Raynes et al., 1991). The intravascular destruction of erythrocytes, which accounts for ~10%-20% of the normal destruction of erythrocytes, releases free hemoglobin (Hb) into the general circulation. The primary function of Hp is to bind to this Hb, thereby preventing the renal excretion of iron and protecting blood vessels from the oxidative effects of this protein (Giblett, 1968). Even when the destruction is mainly extravascular, some erythrocytes still undergo lysis in the intravascular compartment, as shown by the reduced serum levels of Hp in sickle cell diseases and thalassemias (Hillman and Finch, 1992).

The serum concentration of Hp is influenced by age and is generally measurable from three months onwards, with a gradual increase until adult concentrations (30-200 mg dL-1) are reached at 20 years of age (Jayle and Moretti, 1962; Shinton et al., 1965). When not bound to Hb, Hp is cleared from the plasma in ~3.5-5 days, but when bound to Hb, the average time for removal of the complex (mainly by hepatocytes) is ~20 min (Noyes and Garby, 1967; Bissell et al., 1972; Javid, 1978). Measurement of the circulating Hp concentration can be used to determine whether there have been recent episodes of hemolysis since increased Hp consumption during these episodes leads to reduced plasma levels of this protein (Silverman and Christenson, 1994). Because Hp is also a positive acute-phase protein with immunomodulatory properties that may inhibit or stimulate the immune response, the concentration of this protein is elevated in inflammatory and infectious processes and in malignancies (Braeckman et al., 1999).

Protein Structure

Haptoglobin is a tetrameric protein that structurally resembles certain immunoglobulins because it has two light chains (α) and two heavy chains (β) covalently bound to each other by disulphide bridges (S-S) (Malchy et al., 1973; Raugei et al., 1983). Although present in all vertebrates, in humans Hp is characterized by molecular heterogeneity caused by genetic polymorphism. Jayle and Judas (1946) were the first to suspect that there were differences in the structure of Hp molecules and Smithies (1955), using starch gel electrophoresis, identified three main phenotypes: Hp1-1, Hp2-1 and Hp2-2. Subsequently, Smithies and Walker (1956) showed that these phenotypes were controlled by two autosomal codominant alleles identified as HP1 and HP2.

The β-chain of Hp has a molecular mass of 40 kDa (245 amino acids) and is not polymorphic. Haptoglobin polymorphism reflects inherited variations in the α-chain (the smallest chain) of Hp that result from differences between the α1-chain (with 83 amino acids) and the α2-chain (with 142 amino acids) (Kurosky et al., 1980; Maeda, 1991). The α1-chain can be further classified into α1S (slow) or α1F (fast), depending on the electrophoretic mobility. The difference between these chains lies in the amino acids at positions 52 and 53, which are asparagine and glutamic acid in α1S and aspartic acid and lysine in α1F, respectively (Smithies et al., 1962; Connell et al., 1966). This polymorphism results in Hp with different molecular masses, i.e., 86 kDa for Hp1-1, 86-300 kDa for Hp2-1 and 170-900 kDa for Hp2-2 (Lange, 1992; Langlois and Delanghe, 1996).

The polymeric composition of Hp is also type-dependent, with the protein product of the HP1 allele being monovalent and that of the HP2 allele being bivalent. Consequently, Hp occurs as a dimer in Hp1-1 homozygotes, as a linear polymer in Hp2-1 heterozygotes and as a cyclic polymer in Hp2-2 homozygous individuals (Javid, 1965; Langlois and Delanghe, 1996; Frank et al., 2001). These variations in shape and size form the basis of the most commonly used method for phenotyping Hp subtypes (Santoro et al., 1982).

Haptoglobin Genes

The HP locus is located on the long arm of chromosome 16 (16q22) (Robson et al., 1969). The loci corresponding to the α and β chains are linked to each other so that a single mRNA molecule generates a large polypeptide chain that is then cleaved to yield the two Hp chains (Raugei et al., 1983; Koch et al., 2003).

The HP1 allele has five exons while the HP2 allele has seven; the 5th and 7th exons in the HP1 and HP2 alleles, respectively, correspond to the β chain locus (Figure 1). The divergences between HP1S and HP1F are caused by base substitutions in codons 52 and 53 located in the 4th exon (Black and Dixon, 1968; Van der Straten et al., 1984). In contrast, the HP2 allele is a partially duplicated gene derived from a rare unequal crossover between the HP1F and HP1S alleles. This gene is 1.7 kb longer than the HP1 alleles, and the region responsible for encoding from the 11th to the 69th residue (exons 3 and 4 of HP1) is duplicated (Bearn and Franklin, 1958; Smithies et al., 1962; Yang et al., 1983). Combinations of these three alleles yield six distinct genotypes and their corresponding phenotypes, namely, Hp1S-1S, Hp1S-1F, Hp1F-1F, Hp2-1S, Hp2-1F and Hp2-2 (Maeda et al., 1984).

The HP gene belongs to a small multigene family that originated from an ancestral single-copy gene probably after the separation of New World from Old World primates. New World primates have only one HP gene, whereas chimpanzees, gorillas and orangutans have three (haptoglobin, HP; haptoglobin-related, HPR; haptoglobin-primate, HPP) and humans have two genes (HP and HPR) (Maeda and Smithies, 1986; McEvoy and Maeda, 1988). Triplication of the HP locus is believed to have occurred before the separation of Old World monkeys from the family Hominidae (human-chimpanzee-gorilla-orangutan), 25-30 million years ago (mya), while the event that deleted one locus in humans and resulted in the two-gene cluster took place after divergence of the human and chimpanzee lineages, about 5 mya (Maeda and Smithies, 1986; McEvoy and Maeda, 1988). Insertions, deletions, recombinations and gene conversions have contributed to the evolution of the HP gene family (Erickson et al., 1992). Homologous pairings facilitated by exon 5, the longest and most conserved exon of these genes, resulted in unequal crossovers that led to the duplication, triplication and deletion of HP genes (Erickson and Maeda, 1994). Since the HP2 allele apparently occurs only in humans, it is probable that this allele also originated after the separation of humans from other primates (Bowman and Kurosky, 1982).

The Haptoglobin-Related Gene (Hpr)

As mentioned above, in humans the HP gene sequence is duplicated (2.2 kb downstream of the gene itself) on chromosome 16 (Maeda et al., 1984; Muranjan et al., 1998). This second gene is known as the Hp-related gene (HPR). In some individuals of African origin, multiple copies are present (Maeda et al., 1984; Maeda, 1985). The HPR gene differs from the HP gene mainly in that it has a retrovirus-type sequence inserted into the first intron. The promoter region is active and encodes a protein called haptoglobin-related protein (Hpr) (Maeda, 1985), the serum concentration of which is ~5%-10% of that of Hp in healthy individuals.

The Hpr protein is believed to be part of the trypanosome lytic factor (TLF), a toxic subtype of high-density lipoproteins (HDLs) that provides humans with an innate defense against infection by Trypanosoma brucei brucei (Maeda, 1985; Smith et al., 1995), the parasite responsible for Nagana disease in cattle. When Hpr binds to free Hb, it kills the trypanosome via oxidative damage initiated by its peroxidase activity (Smith et al., 1995). Since Hp is the major serum inhibitor of the TLF, the balance between the serum concentrations of Hp and Hpr determines the degree of protection against trypanocidal infection (Smith and Hajduk, 1995).

Muranjan et al. (1998) examined the Hp and Hpr concentrations in sera from patients with paroxysmal nocturnal hemoglobinuria. In this pathology, extensive intravascular hemolysis results in an excess of free Hb in the circulation. As expected, the Hp levels in these patients were much lower than in healthy individuals, but the Hpr levels did not differ significantly, suggesting that Hpr did not bind to Hb. More recently, Nielsen et al. (2006) used surface plasmon resonance to compare the binding affinities of Hp and Hpr recombinant proteins for Hb and found that Hpr competed in a similar manner to Hp for binding to Hb. However, the Hpr-Hb complex is not internalized via the CD163 receptor of macrophages.

The Hp0 Phenotype

The Hp0 phenotype is characterized by the absence or reduced levels of Hp in plasma (referred to as ahaptoglobinemia and hypohaptoglobinemia, respectively) and shows that Hp is not essential for human survival (Koda et al., 1998). This phenotype may be secondary to increased consumption or reduced production of Hp, as occurs during intravascular hemolysis and liver diseases, respectively, or may be genetically determined (Delanghe et al., 1998b; Koda et al., 2000). A study using Hp knockout mice showed that the lack of Hp did not impair the clearance of free plasma Hb, but the induction of severe hemolysis resulted in more serious tissue damage than in normal (control) mice (Lim et al., 1998).

In East Asian populations, genetically determined hypohaptoglobinemia results from an ~28 kb deletion, referred to as HpDel, that extends from the HP gene promoter region to exon 5 of the HPR gene. This deletion was identified in ahaptoglobinemic patients who developed anaphylactic transfusion reactions caused by antihaptoglobin antibodies (Koda et al., 1998, 2000). The homozygous genotype (HpDel/HpDel) corresponds to the complete absence of serum Hp whereas the two forms of hypohaptoglobinemia (Hp2/HpDel genotype and Hp1/HpDel genotype) are associated with extremely low levels of Hp and levels that are approximately 50% of those observed in normal genotypes, respectively. The HpDel gene frequencies in Japanese, Chinese and Korean populations are between 0.15 and 0.30 (Koda et al., 2000).

A more recent study that investigated several other Asian populations also detected HpDel in Mongolians (frequency of 0.08), but could not in populations from Central, Southeast, South and West Asia (Soejima et al., 2007). Possible explanations for the lack of detection in these population include the sample size of the studied populations, the extinction of the HpDel allele in other Asian populations except in East Asia, or the expansion of this deletion to East Asia by chance. Based on the migratory movements that have occurred in that region, it is suggested that HpDel originated in China and from there spread into Mongolia, Korea and Japan (Soejima et al., 2007).

The HpDel allele has not been found in European and African populations. Mutations in the promoter region of the HP gene appear to be the primary cause of congenital ahaptoglobinemia (Teye et al., 2003). In Caucasians, the prevalence of the Hp0 phenotype is estimated to be 0.1% (Langlois and Delanghe, 1996), whereas in Africans it can be as high as 40% or more (Constans et al., 1981; Teye et al., 2004); the occurrence of this phenotype is influenced by acquired ahaptoglobinemia in areas where malaria is endemic and untreated (Boreham et al., 1979). In North Americans of African descent, the frequency of the Hp0 phenotype is ~2.3% (Carter and Worwood, 2007).

Structural Variants

Structural variants of Hp have been described (Carter and Worwood, 2007). For example, Haptoglobin Carlberg was identified in 1958 and is associated with reduced synthesis of the α1S chain (Galatius-Jensen, 1958). Modified Hp2-1 (Hp2-1M) has a different electrophoretic pattern from that of the Hp2-1 phenotype because of its greater number of Hp1 bands, which are heavier and more intense (Connell and Smithies, 1959). This phenotype is generated by the polymorphism of a single nucleotide in the promoter region of the HP2 gene and is more frequent in African populations (Maeda, 1991; Quaye et al., 2006). Giblett (1959) reported that the prevalence of this phenotype in North American Blacks in the Seattle region was 9.8%. Azevedo et al. (1969) studied a population of 541 Afro-descendants from northeastern Brazil and found an association between the HPα2M allele and the presence of hypohaptoglobinemia. The rare Hp Johnson is the result of a crossover between the two Hp2 alleles and causes hypohaptoglobinemia or ahaptoglobinemia. The electrophoretic pattern of this phenotype consists of the Hp1 band and various polymers that migrate slowly (Smithies et al., 1962; Bowman and Kurosky, 1982; Langlois and Delanghe, 1996).

Geographic Distribution of Hp Alleles

There is marked variation in the frequency of HP genes with geographic region (Giblett, 1961; Schultze and Heremans, 1966). The HP2 allele originated in India ~2 mya and propagated around the world as a result of intense genetic pressure, gradually replacing the hegemony of the HP1 allele. This suggests that the HP2 allele may have a selective advantage over the HP1 allele (Schultze and Heremans, 1966). The frequency of the HP1 allele increases from Southeast Asia to Europe and Africa, and from Asia to America, by way of Alaska. In America, the highest frequencies are found in indigenous populations of Chile, Peru, Mexico, Venezuela and on the Brazilian-Venezuelan border, among the Yanomama Indians (Sutton et al., 1960; Nagel and Etcheverry, 1963; Johnston et al., 1969; Nagel et al., 1964; Shim and Bearn, 1964; Schultze and Heremans, 1966; Tanis et al., 1973; Marini et al., 1993).

The equilibrium of the HP1/HP2 polymorphism is broadly constant throughout the world. The allele frequencies in European populations are ~0.43 for the HP1 allele and 0.57 for the HP2 allele; in American populations, the corresponding figures are ~0.54 and 0.46 (Langlois and Delanghe, 1996). Recent studies of populations from southern and southeastern Brazil have revealed allele frequencies of ~0.53 and 0.46 for HP1 and 0.47 and 0.54 for HP2, respectively (Souza et al., 2003; Zaccariotto et al., 2006). Shreffler and Steinberg (1967) found frequencies of 0.48 and 0.47 for HP1 and 0.52 and 0.53 for HP2 among Xavante Indians living in the villages of Simões Lopes and São Marcos, respectively, in central-western Brazil. More recently, Simões et al. (1989) found very high frequencies of the HP1S allele and low frequencies or complete absence of the HP1F allele among Macushi and Içana River Indians in the Amazon region. Table 1 summarizes several studies that have examined the frequency of HP alleles in different populations around the world.

Biological Functions of Hp

The Hp phenotypes have different biochemical and biophysical characteristics and functional efficiencies that account for their distinct antioxidant and immunomodulatory capacities (Langlois and Delanghe, 1996; Frank et al., 2001; Guetta et al., 2007). In the following sections, we discuss the main biological functions of Hp.

Binding of Hemoglobin and Prevention of Renal Damage

Hemoglobin released from erythrocytes is highly toxic and mediates iron-driven oxidative stress and inflammation (Tseng et al., 2004). As indicated above, the main physiological role of Hp is to remove free Hb released by intravascular hemolysis. Haptoglobin and Hb bind to each other to form an essentially irreversible, non-covalently bound, soluble complex characterized by high stability and affinity (1 x 10-15 mol L-1) (Okazaki et al., 1997). Some studies suggest that the β chain of human Hb contains two specific Hp binding sites (residues β11-25 and b131-146) whereas the α-chain only has one Hp binding site (residues α121-127). The Hb αβ dimers bind stoichiometrically to the αβ subunits of Hp (McCormick and Atassi, 1990; Langlois and Delanghe, 1996). Haptoglobin in the circulation system reaches saturation at a free Hb concentration of 500-1500 mg L-1 (Langlois and Delanghe, 1996; Van Vlierberghe et al., 2004).

Free Hb from lysed erythrocytes is eliminated by glomerular filtration, and this can cause renal damage. Hp reduces the loss of Hb and iron because the Hp-Hb complex is not filtered through the glomeruli (Langlois and Delanghe, 1996; Devlin, 1997; Sadrzadeh and Bozorgmehr, 2004; Van Vlierberghe et al., 2004). Once formed, the Hp-Hb complex is quickly removed from the circulation by hepatocytes (90%) and tissue monocytes/macrophages (10%). The specific receptor for the Hp-Hb complex in hepatocytes has not yet been cloned or characterized, but has a high binding affinity for the complex. This receptor apparently recognizes the conformational change in Hp caused by formation of the complex with Hb (Kino et al., 1980). The receptor for this complex in macrophages was recently identified as CD163 (Kristiansen et al., 2001; Horn et al., 2003). After endocytosis, the complex is broken down by lysosomes. Haptoglobin is not recycled, but the heme is degraded by heme-oxygenase (HO) to release iron, which is used to synthesize new proteins such as Hb, and biliverdin, which is subsequently converted into bilirubin (Wagener et al., 2003; Van Vlierberghe et al., 2004). Interleukin-6 plays a very important regulatory role in this process since, in addition to stimulating Hp production, it also increases the expression of CD163 in macrophages and increases the efficiency with which the Hb heme group is degraded (Dennis, 2001).

Protection Against Toxic Radicals

In the Fenton reaction, free iron can react with oxygen to generate superoxide radicals and with H2O2 to generate hydroxyl radicals (Kaplan, 2002). Free iron can also catalyze the oxidation of low-density lipoproteins that can then damage vascular endothelial cells (Grinshtein et al., 2003). The ability of Hp to reduce the damage caused by free radicals is phenotype-dependent (Gutteridge, 1987; Van Vlierberghe et al., 2004). Experiments with purified Hp have shown that the Hp1-1 protein confers greater protection against oxidative damage in vitro (Koda et al., 1998). As the three main Hp phenotypes have the same binding affinities for Hb (Frank et al., 2001), variations in their ability to prevent the release of heme probably reflect the differences in the size of these proteins. Thus, the Hp2-2 protein removes iron to the extravascular space more slowly because it is a larger molecule. Consequently, in individuals with this phenotype (Hp2-2), free Hb remains in the circulation longer and causes greater oxidative stress (Frank et al., 2001).

Inhibition of Nitric Oxide

Nitric oxide (NO), originally referred to as endothelium-derived relaxing factor (EDRF), is a highly reactive gas produced by various types of cells, including vascular endothelial cells and cytokine-activated macrophages (Hibbs et al., 1988). Nitric oxide is involved in the maintenance of vascular tone and also modulates neurotransmitter function in the central and peripheral nervous systems, platelet aggregation and cellular defense (Green, 1995; Sadrzadeh and Bozorgmehr, 2004; Moncada and Higgs, 2006). Free Hb and Hp bound to Hb inactivate NO/EDRF, whereas Hp does not. Consequently, an increase in the level of circulating Hp-Hb may inhibit NO formation and endothelium relaxation, thereby enhancing the risk of cardiovascular disease (Griffith et al., 1984; Edwards et al., 1986; Moncada and Higgs, 2006). The Hp1-1 phenotype may be advantageous in this respect because the Hp1-1:Hb complex is removed from circulation more rapidly than the other Hp complexes (Frank et al., 2001).

Immunomodulation

The enhanced production of Hp during the acute phase of inflammation and infection and tumor growth suggests that this protein has additional functions. Haptoglobin has immunoregulatory properties, with Hp2-2 individuals showing greater immunological reactivity (including greater production of antibodies after vaccination) than Hp1-1 and Hp2-1 individuals (Nevo and Sutton, 1968; Langlois and Delanghe, 1996). Haptoglobin also inhibits prostaglandin synthesis and consequently has important anti-inflammatory properties, although these are less pronounced in Hp2-2 individuals (Langlois and Delanghe, 1996; Braeckman et al., 1999).

Haptoglobin is a powerful suppressor of lymphocyte function, as shown by its ability to inhibit the mitogenic response of lymphocytes to phytohemagglutinin and concanavalin A (Baseler and Burrell, 1983). Different T helper (Th) lymphocyte subtypes, known as Th1 and Th2 cells, are responsible for inducing and regulating the cellular and humoral immune response, respectively. T helper-1 cells produce IL-2 and interferon gamma (IFN-γ) and induce strong IgG responses, thus favouring the cellular immune response, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13 and increase IgE production, thereby mediating a predominantly humoral and eosinophilic response (Abbas and Lichtman, 2003). Arredouani et al. (2003) showed that Hp plays an important role in modulating the balance between Th1 and Th2 lymphocytes (Th1/Th2) by promoting a predominantly Th1 cell response. These cells are more effective in protecting against infections involving intracellular parasites and inhibit the release of Th2 cytokines responsible for defence against extracellular microorganisms. These authors subsequently reported (Arredouani et al., 2005) that Hp selectively modulates the inflammatory response through its ability to suppress the synthesis of TNF-α, IL-10 and IL-12 by monocytes stimulated with lipopolysaccharide (LPS). More recently, Guetta et al. (2007) showed that Hp1-1-Hb induces much greater IL-6 and IL-10 production than Hp2-2-Hb and that the release of these cytokines depends on the binding of these complexes to macrophage CD163 receptors and on casein kinase II (CKII) activity. The action of CKII was differentially regulated by the type of binding between the different Hp-Hb complexes and the CD163 receptor. Based on these findings, Guetta et al. (2007) suggested that Hp1-1 individuals have greater vascular protection than Hp2-2 individuals.

Angiogenesis

Angiogenesis involves the formation of new blood vessels under normal (healthy) and pathological conditions (Cid et al., 1993). Haptoglobin is considered one of the serum angiogenic factors and is necessary for endothelial cell proliferation and differentiation (Dobryszycka, 1997). In arteries, Hp is involved in cell migration and restructuring of the vessel (De Kleijn et al., 2002). Haptoglobin is useful for the treatment of chronic inflammatory conditions and systemic vasculitis because of its ability to stimulate tissue repair and to compensate for ischemia by promoting the growth of collateral vessels. Surprisingly, Hp2-2 is more angiogenic than the other Hp phenotypes (Cid et al., 1993).

Quantification, Phenotyping and Genotyping of Hp

The Hp concentration in humans is generally stable but changes with age. Haptoglobin levels may be affected by the Hp phenotype, with circulating concentrations in the following order Hp1-1 > Hp2-1 > Hp2-2 (Langlois and Delanghe, 1996; Imrie at al., 2006). The level of Hp in fetuses, cord blood and neonates is usually very low (Galatius-Jensen, 1958). Azevedo et al. (1974), in an investigation of the factors that could influence ahaptoglobinemia in Brazilian neonates, detected Hp in only 8% of neonates, with a predominance of the Hp1-1 phenotype.

Haptoglobin plasma levels were initially estimated by measuring the ability of plasma to bind Hb. Radial immunodiffusion is the simplest technique for quantifying Hp (Mancini et al., 1965), although immunonephelometric and immunoturbidimetric assays are now widely used to quantify Hp (Ramakers and Kreutzer, 1976; Fink et al., 1989).

Haptoglobin phenotyping is generally based on electrophoretic separation of the different subtypes according to their molecular size in an appropriate gel medium (Santoro et al., 1982). Smithies (1955) developed the first method for determining the three main Hp phenotypes based on starch-gel electrophoresis with Hb-supplemented serum followed by peroxidase staining. The Hp1-1 protein migrates as a single fast band, while the Hp2-2 protein shows a series of slow bands. The Hp2-1 protein displays an additional series of slow bands and a weak Hp1-1 band (Bowman and Kurosky, 1982; Langlois and Delanghe, 1996). Starch gels were subsequently replaced by polyacrylamide gels (Peacock et al., 1965). Haptoglobin subtyping has also been done by isoelectric focusing and enzyme-linked immunosorbent assay (ELISA) (Leaback and Walker, 1971; Yokoi and Sagisaka, 1990; Levy and Levy, 2004), while molecular methods, such as the polymerase chain reaction (PCR), have been used to determine Hp genotypes (Yano et al., 1998; Koch et al., 2002, 2003; Levy and Levy, 2004). Genotyping methods have the distinct advantage of being useful even when the Hp levels are low (Delanghe and De Buyzere, 2004).

Hp Polymorphism and Diseases

The functional differences arising from the genetic polymorphism of Hp have led to investigation of the influence of Hp subtypes in different human pathologies (Carter and Worwood, 2007). Table 2 summarizes some important studies that have investigated this association, with emphasis on those involving Brazilian populations.

Diabetes Mellitus (Dm)

The increased oxidative stress in diabetic patients results in the oxidation of glucose and the modification of low-density lipoproteins (LDL). These changes may stimulate the production of inflammatory cytokines that have been implicated in the morphological and pathological changes found in macrovascular and microvascular complications (Giugliano and Ceriello, 1996; Levy, 2003).

Different degrees of susceptibility to the development of vascular problems have observed in studies of the antioxidant properties of Hp in diabetic patients, with Hp 1-1 individuals showing better protection against DM than Hp 2-1 and Hp 2-2 individuals. This variation in oxidative capacity were not attributable to differences in the affinity between Hp subtypes and the Hb molecule, but rather reflected the fact that Hp1, probably because of its smaller size and structure, passed more easily through the endothelial barrier to reach extravascular spaces. Consequently, Hp 1-1 individuals were better protected against oxidative stress than Hp 2-1 and 2-2 individuals (Levy et al., 2000; Nakhoul et al., 2001; Asleh et al., 2003; Levy et al., 2004).

Levy et al. (2002) compared the Hp phenotype in type 2 DM patients with macrovascular complications and normal individuals. Diabetic patients with an Hp2-2 phenotype were five times more likely to have cardiovascular complications than those with an Hp1-1 phenotype. An intermediate risk was associated with the Hp2-1 phenotype. In agreement with this, Hp1-1 apparently protects against restenosis after coronary stent implantation in diabetic patients (Roguin et al., 2002). More recently, Suleiman et al. (2005) analyzed the Hp phenotypes in diabetic patients with acute myocardial infarction and demonstrated that the Hp1-1 phenotype was associated with smaller infarct size and lower mortality rates at 30 days. Shor et al. (2007) reported that large and small-artery elasticity indexes were significantly lower and the systemic vascular resistance significantly higher in Hp2-2 compared with Hp2-1 or Hp1-1 type 2 DM patients, indicating a major predisposition to the development of atherosclerosis in homozygotes for the HP2 allele.

The Hp2-2 phenotype is also associated with microvascular complications in both types of DM (Nakhoul et al., 2007). Nakhoul et al. (2000) found that the Hp2-2 phenotype is overrepresented in Israeli type 1 DM patients with diabetic retinopathy, while type 1 and type 2 DM patients with the Hp1-1 phenotype had greater protection against diabetic nephropathy (Nakhoul et al., 2001). Similar findings were reported by Bessa et al. (2007) for Egyptian patients with type 2 DM. Koda et al. (2002), however, failed to detect a protective effect that could be attributed to the HP1 allele in Japanese type 2 DM patients.

Atherosclerosis and Cardiovascular Disorders

The association between Hp phenotypes and heart disease has been investigated for many years. A significant increase has been reported in the incidence of the Hp 2-2 phenotype in high-risk cardiac patients compared to healthy subjects (Gogishvili et al., 1985). Chapelle et al. (1982) showed that the damage after myocardial infarction was more severe in patients with Hp2-2 than in those with Hp1-1 or Hp2-1 phenotypes. Additionally, the survival time in patients with the Hp2-2 phenotype who underwent a coronary artery bypass graft was shorter than for patients with other Hp phenotypes and has been associated with the accumulation of atherosclerotic lesions in essential hypertension (Delanghe et al., 1997).

The Hp2-2 phenotype is a genetic risk factor for coronary atherosclerosis, independently of classic risk factors such as dyslipidemia, hyperhomocysteinemia, cigarette smoking, hypertension and DM (Stein and McBride, 1998; Van Vlierberghe et al., 2004). This phenotype provides less protection against oxidative stress in arteries of patients with atherosclerotic plaques and is considered a risk factor for developing refractory hypertension; patients with this phenotype therefore require more complex antihypertensive drug combinations to control their blood pressure (Delanghe et al., 1995). In addition, serum cholesterol levels in individuals with the Hp2-2 phenotype are higher than in individuals with the other Hp phenotypes (Braeckman et al., 1999).

Studies of the association between Hp phenotypes and peripheral blood disorders suggest that the Hp2-2 phenotype is more common in peripheral occlusive disorders. Curiously, Hp2-2 patients with severe atherosclerotic lesions subjected to a treadmill stress test reported longer maximal walking distance than patients with other Hp phenotypes, a finding that could be explained by the fact that the Hp2-2 molecule is more angiogenic than the other Hp molecules (Delanghe et al., 1999). These different functions and biological capacities of Hp may be used as a predictor of the susceptibility to cardiovascular disorders and patient prognosis.

Cancer

Several studies have reported a correlation between Hp phenotypes and cancer. Bartel et al. (1985) showed that the prevalence of breast tumors was higher in women with the Hp1-1 phenotype, and Awadallah and Atoum (2004) concluded that the distribution of the Hp phenotype in breast-cancer patients depended on the family history, the HP1 and HP2 allele frequencies being higher in patients with familial and non-familial breast cancer, respectively. The HP1 gene is overrepresented in ovarian carcinoma (Dobryszycka and Warwas, 1983), and an association has been reported between the Hp2-1 phenotype and a family history of ovarian carcinoma (Fröhlander and Stendahl, 1988).

In some studies, the Hp2-2 frequency was significantly lower in patients with pulmonary adenocarcinoma and bladder carcinoma than in normal subjects (Beckman et al., 1986; Benkmann et al., 1987), whereas a significantly higher frequency of Hp2-1 and Hp2-2 phenotypes was found in patients with esophageal and gastric cancer (Jayanthi et al., 1989).

Several authors have examined the correlation between Hp phenotypes and different types of leukemia. Nevo and Tatarsky (1986) investigated Hp phenotypes in patients with the four most common types of leukemia, namely, acute lymphatic (ALL), chronic lymphatic (CLL), acute myeloid (AML) and chronic myeloid (CML) leukemia. A significantly higher frequency of the Hp1-1 phenotype was observed among leukemia patients with ALL, AML and CML, but not among those with CLL. Fröhlander (1984) found no association between Hp phenotypes and leukemia but observed a significantly higher frequency of ahaptoglobinemia in these patients. A low Hp2-2 frequency has been observed in patients with IgA myeloma (Germenis et al., 1983).

Infectious Diseases

Several studies have demonstrated that Hp polymorphism may play a role in a number of infectious diseases. Haptoglobin can act as a natural bacteriostat by preventing the consumption of iron that is necessary for the growth of some pathogenic bacteria such as Neisseria meningitides, Campylobacter jejuni and Bacteroides fragilis (Eaton et al., 1982; Pickett et al., 1992; Otto et al., 1994; Lewis and Dyer, 1995). Eaton et al. (1982) reported that the simultaneous administration of Hp in rats inoculated intraperitoneally with pathogenic Escherichia coli and Hb protected the animals against death.

Kasvosve et al. (2000) showed that in a logistic regression model the odds of patients with tuberculosis dying were 6.1 times greater in individuals with the Hp 2-2 phenotype than in those with the Hp 1-1 phenotype. Furthermore, the Hp2-2 phenotype was overrepresented among patients with large cavities created by tissue destruction, more advanced dissemination and the presence of nephrotic tuberculosis (Fedoseeva et al., 1993; Ubaidullaev et al., 2002).

Some families of integrin adhesion receptors such as CD11a-c and CD18 are involved in cell-to-cell viral transmission and contribute to variations in the survival rates after HIV infection. The identification of Hp as an alternative ligand for CD11b/CD18 suggests that this protein plays an important role in HIV infection (El Ghmati et al., 1996; Quaye et al., 2000a). In addition, the residual iron circulating in the plasma of HIV-seropositive patients could enhance Hb-driven oxidative stress, thereby favoring viral replication and transmission. Delanghe et al. (1998a) reported that HIV-seropositive patients with the Hp2-2 phenotype had a higher mortality and worse prognosis than patients with other phenotypes.

Louagie et al. (1996) reported an association between hepatitis C and Hp polymorphism (Hp1-1 was overrepresented) in patients with the chronic form of this disease. This finding suggests that the Hp phenotype may influence the clinical evolution of hepatitis C. Interestingly, Hp2-2 individuals develop lower levels of antibodies after vaccination against hepatitis B than those with Hp1-1 or Hp2-1 phenotypes (Louagie et al., 1993).

Elagib et al. (1998) reported a significant increase in the incidence of Hp1-1 in Sudanese patients with uncomplicated and complicated (cerebral) falciparum malaria. The phenotypic frequency distribution among patients was 60.8% for Hp1-1, 29.7% for Hp2-1 and 9.5% for Hp2-2, while in healthy (control) individuals from the same region it was 26.0%, 55.8% and 18.3%, respectively. Quaye et al. (2000b) also found an association between Hp1-1 and severe P. falciparum malaria in patients from the coastal region of Ghana. Minang et al. (2004) examined the influence of Hp phenotypes on susceptibility to placental infection by P. falciparum in pregnant women at delivery in western Cameroon and found that Hp1-1 women had a higher prevalence of parasites in peripheral blood and in the placenta.

Neurological Diseases

The functional differences in Hp that are related to genetic polymorphism may be linked to the severity and frequency of seizures in patients with epilepsy. The etiology of most seizures is unknown, and Hp is a promising candidate to explain the differences in susceptibility and resistance to convulsive disease (Sadrzadeh et al., 2004). Microhemorrhagic events may occur in the brain, leading to the accumulation of iron released from Hb. This iron can enhance the formation of reactive oxygen species, increase neuronal excitability, and stimulate membrane lipid peroxidation in the brain, with consequent seizures. Depending on the Hp phenotype, the clearance of intracerebral Hb may not be efficient, and the antioxidant capacity of the interstitial fluid may be compromised (Saccucci et al., 2004). Panter et al. (1984) showed that hypohaptoglobinemia was associated with epileptiform seizures. Sadrzadeh et al. (2004) reported an association between the Hp2-2 phenotype and recurrent seizures in epileptic patients who had one or more idiopathic seizures per month. Saccucci et al. (2004) reported that the Hp1-1 genotype was underrepresented in children with idiopathic generalized epilepsy (IGE) compared with healthy children. Idiopathic generalized epilepsy is linked to a complex pattern of inheritance, and the generalized seizures are probably related to multiple gene-gene and gene-environment interactions. In IGE, the small size of Hp1-1 allows this protein to diffuse in the interstitial cerebral fluid more readily than the other Hp subtypes, thereby protecting its carriers against IGE.

Association Studies In Brazilian Populations

A few studies have examined Hp polymorphism and its association with diseases and systems, e.g., blood groups, in Brazil. Schwantes et al. (1967) found no significant association between Hp polymorphism and Hansen's disease in a large series of patients (~1000) compared with healthy individuals (control group) from southern Brazil.

Kirk et al. (1970) found a significantly higher frequency of the Hp1-1 phenotype in children from northeastern Brazil with ABO-incompatible parental combinations than in children with ABO-compatible parents. These authors concluded that the higher levels of Hp1-1 protein in Hp 1-1 children probably enhanced their chances of surviving postnatal hemolytic disease caused by ABO incompatibility since this protein could reduce iron loss and kidney damage during hemolysis.

Ayres et al. (1976) found no significant differences in the distribution of Hp phenotypes among filarial-positive and filarial-negative individuals. Similarly, Beiguelman et al. (2003) reported no significant differences in the Hp haplotype distribution among individuals infected by Plasmodium in the western Amazon compared with non-infected individuals.

In contrast to previous studies (Nevo and Tatarsky, 1986; Mitchell et al., 1988), Campregher et al. (2004) found no association between leukemia (ALL, CLL, AML and CML) and the higher frequencies of the Hp1 allele in these patients in southeastern Brazil, although the p-value for patients with CLL tended towards significance. In contrast, ahaptoglobinemia was more frequent among these patients, in agreement with the findings of Fröhlander (1984).

Calderoni et al. (2006) investigated the frequency of Hp phenotypes in patients suffering from indeterminate, chronic cardiac, chronic digestive or chronic 'combined' (i.e. cardiac plus digestive) forms of Chagas' disease (American trypanosomiasis) and found that the Hp2-2 phenotype was more frequent in the overall group of patients, in patients with the indeterminate form of the disease and in patients with the chronic combined form.

Zaccariotto et al. (2006) found no significant influence of the Hp genotypes on the iron status, negative and positive acute-phase serum protein concentrations, T-CD4+ lymphocyte counts and viral loads in HIV-seropositive patients and healthy HIV-seronegative individuals in southeastern Brazil. Similarly, Wobeto et al. (2007) observed no significant relationship between the frequency of the Hp genotype in type 1 and type 2 DM patients with and without diabetic retinopathy.

Concluding Remarks

Haptoglobin is a positive acute-phase protein with antioxidant and immunomodulatory properties. Although there is considerable evidence that the different Hp subtypes may be associated with the outcome of many important disorders, the findings for different populations are often divergent because of the large number of variables involved, including the ethnic composition and population homogeneity, the number of individuals analyzed, the methods used for genotyping and phenotyping, the complex physiopathology of the target disorder, and the therapeutic measures used in different health systems, particularly for treating infectious diseases. A better understanding of the functional importance of Hp molecules would be gained if these variables were well-controlled.

Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant no. 05/02383-8).

Received: October 26, 2007; Accepted: January 24, 2008.

Associate Editor: Francisco Mauro Salzano

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  • Send correspondence to:
    Maria de Fátima Sonati
    Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas
    Caixa Postal 6111
    13083-970 Campinas, SP, Brazil
    E-mails:

Publication Dates

  • Publication in this collection
    18 Aug 2008
  • Date of issue
    2008

History

  • Accepted
    24 Jan 2008
  • Received
    26 Oct 2007
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