Role of Haptoglobin in Health and Disease: A Focus on Diabetes Mark MacKellar1 and David J. Vigerust1,2

■ IN BRIEF Prospective identification of individuals with diabetes who are at greatest risk for developing complications would have considerable public health importance by allowing appropriate resources to be focused on those who would benefit most from aggressive intervention. Haptoglobin (Hp) is an acute-phase that is crucial for the elimination of free and the neutralization of oxidative damage. In the past two decades, associations have been made between polymorphisms in Hp and complications arising from diabetes. Individuals with polymorphism in Hp have been shown to have significantly higher risk of developing cardiovascular disease. This review summarizes the current literature on the role of Hp in health and disease, with a focus on diabetes.

ecent epidemiological studies ifications and medication regimens have showed that the diabetes to reduce hyperlipidemia and hyper- Repidemic affects 415 million tension. One area of considerable people worldwide, and this figure is interest in the clinical and research expected to increase to nearly 642 community is the development of million people by 2040 (1). Patients improved screening tools to identify afflicted with diabetes often are more and mitigate cardiovascular risk. One susceptible to a host of multi-organ such area that has had considerable complications that arise as a result of interest is the predictive value of hap- microvascular and macrovascular dys- toglobin (Hp) screening in function. These complications equate cardiovascular risk. to the leading cause of morbidity and Polonovski and Jayle first mortality, in the form of accelerated described the biochemical properties atherosclerotic disease. Dysregulation of Hp more than 75 years ago (5–7). in glycemic control and subsequent Since that initial description, numer- alterations to the vascular endotheli- ous important biological functions um are known to be associated with have been described for Hp. Hp is an 1MyGenetx Clinical Laboratories, Franklin, α TN all grades of atherosclerotic disease acute-phase 2- with a (2,3). Accelerated atherosclerosis is major biological function of binding 2Vanderbilt University School of Medicine, Department of Neurological Surgery, prevalent in this patient population, free hemoglobin (Hb) with very high Nashville, TN contributing to >75% of the mortality affinity to prevent the loss of iron fol- Corresponding author: David J. Vigerust, seen among people with diabetes (4). lowing intravascular (8,9) [email protected] In the past decade, interventions and to prevent Hb-mediated renal DOI: 10.2337/diaclin.34.3.148 to obtain stricter glycemic control injury (10–12). The binding of Hp to have been attempted with debatable free Hb forms a stable complex with ©2016 by the American Diabetes Association. Readers may use this article as long as the work is success. In addition to stricter glyce- very high affinity that is cleared from properly cited, the use is educational and not for mic control measures, attempts have circulation by the system profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 for been made to reduce cardiovascular and CD163-positive macrophages, details. risk by implementing lifestyle mod- Kupffer cells, and hepatocytes (13,14).

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In its role as a clearance protein, Hp removes the oxidative potential of the iron contained in the Hb molecule. Hp is present in the serum of all , but polymorphism is found only in humans (15). The allelic differences seen in humans arise from a crossover duplication of exons 3 and 4, resulting in an Hp1 with 5 exons and an Hp2 allele with 7 exons (Figure 1) (16). Three major are produced and ■ FIGURE 1. Structural representation of the Hp Del, 1, and 2. Hp have been identified by gel electro- exonic sequences are denoted by numbered and shaded boxes. Intronic phoresis: Hp1-1, Hp1-2, and Hp2-2 sequences are denoted by a solid line. Exons 3 and 4 of the Hp1 allele have FEATURE ARTICLE (17,18). Hp Del has also been described been duplicated in the Hp2 allele, giving rise to exons 3–6. in Japanese, Chinese, and Korean populations but has not been found produced proinflammatory cytokines There is sufficient Hp in circu- in African or European populations such as (IL)-1, IL-6, and lation (38–208 mg/dL) to bind and (19–21). Several minor genotypes -α (TNF-α) clear 3 g of Hb, which would pre- (Hp1-Johnson, Hp1-M, and Hp0) (14,29,30). In addition to induction vent free Hb circulation in the body have also been described (22). The by cytokines, glucocorticoids, cat- (44). CD163 expression by these cells three predominant genotypes display echolamines, and hypoxia also can is induced by inflammation and the differing structures and biological activate the expression of Hp (31,32). release of cytokines such as IL-1 and effects, as described below. Despite largely being a serum protein, IL-6. IL-6 plays an especially import- Molecular Structure and Hp is also detected in urine, synovial ant function in that it is important in Regulation fluid, ascites fluid, cerebrospinal fluid, the stimulation of Hp production and The human for Hp is located on and pleural fluid (33). the modulation of CD163 expression on the cell surface (45–47). CD163 16q22 and consists of Functions of Hp three structural alleles, the products is downregulated by TNF-α, IL-4, The hallmark function of Hp is to of which are Hp1F, Hp1S, and Hp2 and interferon γ (48). Regulation of facilitate Hb clearance. Hb is the (23). The products of the Hp1F and this process is tightly controlled by prominent involved in Hp1S alleles differ by only one ami- the release of immunomodulatory no acid, whereas the Hp2 allele is the transporting oxygen in the circulatory molecules. result of a fusion of the Hp1F and system and mediates reactive oxygen Hb that is bound with Hp for Hp1S alleles. Transcription and trans- and nitrogen species detoxification clearance is internalized, processed, lation occurs as a single polypeptide (34,35). Free Hb released into the and degraded to release for fur- that is post-translationally processed blood is a natural phenomenon as- ther processing by hemoxygenase-1 to into a smaller α chain and a larger sociated with intravascular hemolysis release iron where it can be recycled β chain that are linked by a that occurs during the destruction to construct new Hb . When bridge (24). However, the presence of of senescent red blood cells (RBCs), not bound to Hb, Hp is cleared from 6 the Hp1 and Hp2 alleles in humans which occurs at a rate of 2 × 10 the plasma in 3–5 days. When bound gives rise to Hp1-1 dimers, Hp1-2 RBCs per second (36,37). A variety of to Hb, the average time for removal heterodimers, and Hp2-2 dimers. severe complications can result from of the complex is ~20 minutes The estimated frequency of Hp1-1 is intravascular hemolysis when accom- (49,50). Hp is not recycled during 15–18%, Hp2-1 is 46%, and Hp2-2 panied by other comorbidities such this clearance process, but rather is is 38% (25). as diabetes, infectious disease, trau- degraded, and de novo protein pro- Hp synthesis is principally con- ma, and cancer (38,39). Hp forms a duction occurs to resupply the blood ducted in the , but expression strong noncovalent complex with Hb and tissue (51). In the absence of a is also seen in the , , , (Hp-Hb complex) that results in its clearance mechanism, free Hb can , and (26–28). removal via the reticuloendothelial catalyze the formation of free radi- The expression of Hp can be increased system and receptor-mediated endo- cals and mediate the destruction of in the presence of growth hormone, cytosis via CD163 on hepatocytes, cellular constituents and extracellular insulin, and bacterial endotoxin and Kupffer cells, and tissue macrophages macromolecules and promote the oxi- in the expression of macrophage- (40–43). dation of LDL cholesterol (37).

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Antioxidant Activity in people with diabetes is of special ciated with celiac disease and type 1 Hp binds to free Hb with perhaps the concern. In particular, the Hp2-2 diabetes (68,69). Recently, studies by highest affinity in nature (9,52,53). genotype is considered to be a major Zhang et al. (70) and Moreno-Nava- A variety of unfavorable consequenc- susceptibility gene for people with rette et al. (71) have suggested that es can arise when free iron is present type 2 diabetes because it results in serum levels of proHp are elevated in in the circulation and in tissues. For reduced capacity (62). people with type 2 diabetes and that some time, it has been known that Immunoregulatory Activity circulating levels of proHp contribute iron overload can contribute to the to insulin resistance in obesity. The The role of Hp as an acute-phase pro- development of diabetes and athero- elevations in proHp are associated tein brings to light its possible immu- sclerosis (54–57). The pathophysiol- with intestinal permeability, dyslip- noregulatory activity. Dating back as ogy with respect to iron arises from idemia, inflammation, and insulin far as 1968 with the work of Nevo the ability of iron to participate in resistance. the generation of powerful oxidant and Stutton (63) and, more recently, species such as hydroxyl radical (58). the work of Langlois and Delanghe Angiogenesis and Iron participates in the Haber-Weiss (64), individuals of Hp2-2 genotype Lymphangiogenesis reaction to convert reactive oxygen demonstrated enhanced immune Impaired wound healing is a known species (ROS) such as superoxide and function. For example, Hp2-2 indi- major complication of diabetes and hydrogen peroxide to more powerful viduals display a greater response to is caused by apoptosis, cellular infil- species such as hydroxyl radical (56). vaccination by producing higher lev- tration, and reduced angiogenesis. Free iron can be a detrimental catalyst els of protective (65). Hp Recent studies have demonstrated in lipid peroxidation because it can also has been described by Langlois reduced lymphangiogenesis and an- both initiate and amplify the process and Delanghe as having inhibitory giogenesis during diabetic wound of lipid peroxidation. activity in the synthesis of prosta- healing (72–74). Hp is known to The initiation step can be induced glandins and, as a result, having anti- play a role in angiogenesis accord- by two different iron-dependent inflammatory properties (64). ing to Cockerill et al. (75). A study mechanisms. The hydroxyl radi- Hp has been shown to have by Oh et al. (76) demonstrated that cal-dependent mechanism, which powerful regulatory activity on lym- proHp can upregulate the expression has been adopted by most as the phocytes. For example, Arredouani et of vascular endothelial growth factor predominant mechanism for lipid al. (66) and Guetta et al. (67) have (VEGF) and VEGF receptor 2 and peroxidation (59), and an alternate demonstrated that Hp plays a role in increase endothelial sprouting and hydroxyl radical-independent mech- the balance between T helper-1 (Th1) branching. These findings suggest anism, which has also been proposed and T helper-2 (Th2) by heavily pro- that proHp can promote angiogen- and places iron-oxygen complexes moting a strong Th1 cell response. esis via the VEGF signaling pathway. rather than hydroxyl radical as the These studies demonstrated that Cid et al. (77) observed that sera initiator of lipid peroxidation (60). the Hp1 allele, when complexed to from patients with systemic vasculitis These conversions can have damaging Hb, stimulates the secretion of sig- stimulated angiogenesis in an in vitro effects to the tissue. nificantly more IL-6 and IL-10 than model. Serum Hp level in vasculitis The ability of Hp to reduce the the Hp2 allele. A Th1 response is patients was shown to correlate with tissue-damaging effects of free more effective in protecting against both disease and angiogenic activity. radicals is genotype-dependent. intracellular parasites and inhibits The increased levels of Hp found in Investigations by Melamed-Frank the release of Th2 cytokines, which chronic inflammatory conditions et al. demonstrate that Hp1-1 has a are responsible for defending against may play an important role in tis- greater capacity to protect against extracellular pathogens. These find- sue repair. In systemic vasculitis, for oxidative damage despite the fact that ings suggest that patients with Hp1 example, Hp might compensate for all three genotypes have the same alleles are more efficient at protecting ischemia by promoting the develop- binding affinity (61). The crucial -dif against infection. ment of collateral vessels (77). ference is the accessibility of the Hp In the context of immune- Neovascularization resulting from molecule to the extravascular space. mediated diseases, Crohn’s dis- angiogenesis may be pathologically Size differences in the molecules serve ease, ulcerative colitis, rheumatoid important in the context of diabetes. as an exclusionary mechanism; con- arthritis, and systemic lupus erythe- Pathological angiogenesis enhances sequently, in individuals with Hp2-1 matosus all have been linked with disease progression and increases or Hp2-2, free Hb remains in circu- polymorphisms in Hp. For example, macrophage infiltration and vessel lation for a protracted period of time prohaptoglobin-2 (proHp), which wall thickness, leading to hypoxia and causes greater oxidative stress is proteolytically cleaved to Hp2 by and interplaque rupture (78,79). (61). The antioxidant capacity of Hp site-specific cleavage, has been asso- Lipid-rich RBC membranes and free

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Hb are physiologically detrimental in have demonstrated that patients can bearing on the ultimate outcome of the context of diabetes and athero- have a greater susceptibility to ma- infection. sclerosis. Neovascularization of the laria and the development of severe Hp genotype has also been asso- atherosclerotic plaque may be driven complications depending on their Hp ciated with intracellular pathogens. by Hp or proHp, leading to greater genotype (85–88). Diabetes has been recognized as an risk in people with diabetes. Pathogens such as Corynebacterium important risk factor for several intra- Blockade of Nitric Oxide diptheriae and Staphylococcus aureus, cellular pathogens (98). For example, patients with Hp2-2 have a higher Nitric oxide (NO) is a gas produced which require iron for growth, are degree of mortality from HIV, with by a variety of cell types that is in- known to take advantage of the a median survival time of 11 years volved in several important physio- Hp-Hb complex for their metabolic for people with Hp1-1 or Hp2-1 logical activities. NO is involved in activity (89,90). The reduced activity compared to 7.3 years for those with vascular tone, modulates neurotrans- of Hp2 to clear free Hb may allow Hp2-2. Hp2-2 patients also had sig- mitter function in the central and pe- these bacteria to use this iron source,

nificantly higher HIV viral titers than FEATURE ARTICLE ripheral nervous systems, and partic- contributing to enhanced coloniza- those with other genotypes (99). Hp ipates in cellular defense and tion and growth. Pishchany et al. genotype also has been investigated aggregation (80,81). Both free Hb and (91) have demonstrated that S. aureus in HIV patients in the development the Hp-Hb complex inactivate NO, can grow in a manner that is entirely of Kaposi sarcoma (KS). KS is caused whereas Hp does not affect NO. As a dependent on the ability to bind Hb, by herpes virus 8, an opportunistic result, an increase in the level of cir- extract heme, pass heme through the infection rarely seen outside of immu- culating Hb or Hp-Hb complex may bacterial cell envelope, and degrade nocompromised patients. Speeckaert result in the depletion of NO and the heme in the cytoplasm. The ability et al. (100) examined the effect of Hp lack of endothelial relaxation contrib- of different bacteria to use iron from genotype and demonstrated that the uting to cardiovascular disease (CVD). Hb may allow for the generation of Hp1-1 genotype conferred the great- Patients with an Hp1-1 genotype soft tissue infection when free heme est risk to the development of KS, may experience benefits over Hp2-1 is not removed after RBC hemolysis. followed by Hp2-2 and Hp2-1. In or Hp2-2 carriers because the Hp1-1 People with diabetes are especially contrast, Speeckaert et al. (101) in an Hp-Hb complex will be cleared from susceptible to bacterial infections, earlier study demonstrated that Hp1-1 circulation more efficiently than especially urinary tract, respira- provided the greatest protection from other Hp complexes. The more rapid tory, and soft tissue infections. For Epstein-Barr virus, and Hp2-2 has clearance enhances the availability example, S. aureus is known to cause the greatest association as determined of NO to carry out its physiological both respiratory infections and uri- by serum titer. In animal models of functions. One illustration of the nary tract infections that can lead influenza, there is significant evidence benefits of one Hp genotype over to bacterial nephritis. Addtionally, that Hp is upregulated in clinical dis- another was seen in a recent report S. aureus is the most common soft ease. This has been found in pigs and by Sertorio et al. (82) showing that, tissue infection in people with diabe- ferrets, which share a lung physiology in patients with preeclampsia, Hp1-1 tes (83,92,93). These findings could similar to that of humans (102,103). played a protective role by reducing be especially important in the con- Significant observations regarding NO scavenging. Patients with Hp2-1 text of diabetes complications, CVD, bovine respiratory disease have been and Hp2-2 appeared to have aggrava- surgical interventions, and trauma. In associated with increased Hp pro- tion of preeclampsia, in part because general, host innate immune mecha- duction (104). These observations in of reduced NO bioavailability. nisms, including Hp, would restrict the accessibility of iron to pathogens, respiratory infection are especially rel- Disease Implications of Hp thereby removing one important bac- evant given the recent report of Hp Polymorphism terial growth requirement (94,95). as part of the human lung surfactant Infectious Disease Finally, Hp2-2 patients also have system, in which it co-localizes with surfactant protein B (105). As seen Diabetes is a predisposing factor for been found to have higher mortality through these few examples, suscepti- infections. People with diabetes have and poorer outcomes from tubercu- bility to infectious disease is, in part, a two to four times greater risk of losis and Hanson’s disease (leprosy) dependent on Hp genotype, and this systemic infection than people with- than other genotypes (88,95–97). is especially important in people with out diabetes (83,84). Variation in Given its role as an acute-phase diabetes and Hp polymorphism. Hp genotype is also implicated as a protein, the participation of Hp in contribution to mortality from both various pathogenic infections is well Neurology extracellular and intracellular patho- documented, and the specific geno- Diabetes has been associated with gens. For example, several studies type that a patient carries has direct dementia and neurodegenerative

VOLUME 34, NUMBER 3, SUMMER 2016 151 FEATURE ARTICLE disorders such as Alzheimer’s disease study, so a future investigation will of stroke in people with type 1 dia- (AD) and Parkinson’ disease (PD) be needed to determine the impact of betes and the Hp1-1 genotype. In an (106,107). Although the mechanisms Hp1 versus Hp2 on AD pathogenesis. earlier study (121), this same group remain unclear, type 2 diabetes can Brain atrophy, reduced cerebral glu- described an increased risk for CVD exacerbate and lead to progression of cose metabolism, and central nervous in people with the Hp2-2 genotype the neurodegenerative process. One system insulin resistance are all fea- compared to those with the Hp1-1 possible common mechanism is oxi- tures of AD, PD, and type 2 diabetes genotype. Staals et al. (122) likewise dative stress (108). In addition to this (113,114). suggested an increased risk for lacu- commonality in pathogenesis, there Finally, several studies have exam- nar stroke depending on patients’ Hp is also evidence that AD itself can ined the effect of Hp genotype on the genotype. The aforementioned study promote insulin resistance within the outcome and resolution of intracere- by Holme et al. (118) established a brain (108). bral hemorrhage. Murthy et al. (115) twofold increased risk for stroke and a Given the common thread of oxi- recently reported that patients with 1.5-fold increased risk for HF. Hp2-2 dative stress and the role of Hp in the the Hp2-2 genotype experience worse has been associated with higher total management of oxidative reactions, outcomes after intracerebral hemor- serum and free cholesterol concen- several recent studies have demon- rhage. These results were supported trations, reduced graft survival in strated the relationship of Hp with by another study by Kantor et al. patients undergoing coronary artery neurodegenerative pathologies. In (116) in the context of subarachnoid bypass, and a greater risk of restenosis fact, Hp genotype has been impli- hemorrhage, in which patient out- after stent implantation (Hp2-2 36% cated in greater susceptibility to comes were worse in those with the vs. Hp2-1 31%) (123–125). idiopathic PD (109,110). There are Hp2-2 genotype. Hp2-2 is a clear genetic risk fac- also several reports of Hp involve- tor for the development of aneurysm, ment in the pathogenesis of AD. Cardiology coronary atherosclerosis, and unsta- The accumulation of β- in Hp genotype has been consistently ble carotid stenosis independent of, the brain is a driving force for AD associated as a marker and risk fac- or in connection with, many of the pathogenesis. Spagnuolo et al. previ- tor for CVD. In a study by Chapelle classical risk factors, including dys- ously reported that Hp could bind to et al. (117), patients with the Hp2-2 lipidemia, hypertension, diabetes, apolipoprotein E (ApoE) and impair genotype had more severe myocardial smoking, and hyperhomocystenemia its function in cholesterol homeo- infarction. Hp was later examined in (12,126,127). In one study involving stasis (111). Immunoprecipitation a prospective study of >342,000 pa- male patients with diabetes, Lioupis and immunoblotting has shown tients over 11.8 years. Hp was shown et al. (128) demonstrated that that Hp and β-amyloid form com- to be a significant risk factor of acute patients had a higher serum level of plexes in brain tissue from patients myocardial infarction (AMI), stroke, homocysteine and that those with the with AD. The interaction between and heart failure (HF) (118). Data Hp2-2 genotype had a higher concen- ApoE and β-amyloid was shown to from this study established an asso- tration of iron in the atherosclerotic be crucial for limiting β-amyloid ciation of Hp in these cardiovascu- plaque. These findings suggest that neurotoxicity and for promoting its lar events that was stronger for men increased intraplaque iron deposi- clearance. Spagnuolo et al. further than for women. Hp was almost as tion may be responsible for increased demonstrated that Hp, rather than predictive as total cholesterol for oxidative stress and instability of the impairing ApoE binding to β-amy- AMI and about as predictive as total carotid plaque. loid, promotes the formation of the cholesterol of stroke, with a stronger Additionally, Hp is a risk fac- complex between β-amyloid and relationship to ischemic disease than tor for developing refractory ApoE2, ApoE3, or ApoE4 (111). to hemorrhagic stroke where a 4.2- hypertension in patients with exist- Hence, the suggestion from this study fold increase in risk was observed in ing hypertension (129,130). Data is that the risk of developing AD not ischemic disease. Haas et al. (119) demonstrate that patients with the only might be linked to the different likewise established an association Hp2-2 genotype require more anti- ApoE isoforms, but also may rely on with Hp as a potential prognostic hypertensive therapy to control blood the level and type of Hp. Song et al. biomarker in AMI. In summary, Hp pressure than do patients with other (112) reported a significantly higher genotype carried as much predictive genotypes. Patients with the Hp2-2 level of serum Hp in patients with value as total cholesterol for risk of genotype also require more support AD than in healthy control subjects. AMI and stroke. and follow-up than do patients with Their results support the hypothesis HF and stroke also have been alternate Hp genotypes (129,130). that oxidative stress is a key event in associated with Hp genotype Conversely, patients with the Hp1-1 the pathogenesis of AD. The specific (118,120). Costacou et al. (120) genotype have a lower rate of compli- genotypes were not examined in this described a borderline increased risk cations than do hypertensive patients

152 CLINICAL.DIABETESJOURNALS.ORG m a c k e l l a r a n d v i g e r u s t with either the Hp2-1 or the Hp2-2 diabetic retinopathy in people with determine the effects of this genotype genotype (130). type 2 diabetes. In patients with nor- versus nonhomozygous carriers. The literature strongly supports mal blood pressure, Mogarekar and A rapid test can be employed to the hypothesis that the Hp2-2 gen- Hampe (137) showed an increased initiate a therapy such as vitamin E or otype provides much less protection risk for the development of severe vitamin C to minimize the progres- from oxidative damage to arteries in retinopathy in those with the Hp2-2 sion of CVD by as much as 30–40% patients with atherosclerotic plaques. genotype. When compared to other (143). Initiation of 400 IU of vitamin The Hp2-2 genotype also confers genotypes, this study showed a graded E has been shown effective in reduc- additional CVD risk, as well as other risk relationship with the number of ing cardiovascular events (12,144). complications, including aneurysm, Hp2 alleles. The antioxidant activity of vitamin carotid plaque rupture, myocardial Hp genotype determination, E neutralizes the oxidative capacity infarction, and decreased survival therefore, can be valuable in the of free heme and serves as a surro- after coronary artery bypass. It has assessment and management of gate for Hp activity (145). Free heme become clear in the past 20 years diabetic retinopathy. Research has can result in the oxidation of LDL FEATURE ARTICLE that Hp can be considered a predic- clearly demonstrated that blindness particles and lead to the growth and tor of susceptibility to cardiovascular from diabetes is preventable with instability of atherosclerotic plaque. disorders and a measure of patients’ early diagnosis, clarification of risk Moderate doses of vitamin C and E prognosis and outcomes. factors, and timely photocoagulation can be effective in stabilizing oxida- Diabetes where appropriate. Hp genotyping tive stress and reducing the levels of can allow for earlier identification The generation of ROS has a signifi- circulating free radicals (12,145). The of and prompt early intervention for cant role in the generation of vascular current methodology for determining patients who may suffer from diabetic complications in people with diabetes genotype is gel electrophoresis, which retinopathy. (61). Complications in people with is time-consuming and not optimal diabetes resulting from HP genotype Diagnostic Implications of Hp for large patient volume or commer- include cardiovascular events, reti- Plasma Hp concentrations have been cial diagnostic purposes. A method nopathy, and nephropathy. In stud- examined for a variety of pathogenic developed by Levy et al. (146) uses ies of patients on hemodialysis, Levy disorders. Both high and low levels of an enzyme-linked immunosorbent and others (131,132) have described Hp are indicative of clinical condi- assay (ELISA) to characterize the a protective effect in patients with tions. Elevated plasma concentrations Hp genotype. This ELISA method the Hp1-1 genotype. Two indepen- have been described in cases of trau- is a user-friendly, accurate diagnostic dent studies by Levy et al. (133,134) ma, burn, inflammation, and cancer tool for determining Hp genotype in showed that Hp genotype correlates because of the acute-phase nature of the research environment but has not with vascular complications. For ex- the protein and its role in the removal been employed in a commercial diag- ample, the Hp1-1 genotype protects of oxidative species from the circula- nostic capacity. against vascular injury as a conse- tion (33,61,138). Plasma levels are New methods for high-volume quence of increased antioxidant ac- high beginning several days after the patient genotyping allow for rapid tivity compared to Hp2-1 or Hp2- inflammatory or traumatic insult and screening and early implementation 2. Similar results were described by return to normal within several weeks of alternate antioxidant therapy and Szafranek et al. (135), who found that (139). Conditions in which Hp is de- provide a tremendous benefit to peo- Hp was a major susceptibility gene creased include malnutrition, hemoly- ple with diabetes. for diabetic vascular complications. sis, hepatic disease, allergic reactions, The Hp2 genotype has been report- and seizure disorders (139–142). Conclusion ed to be associated with an increased Given the involvement of Hp in The most thoroughly characterized risk for cardiovascular events such the pathogenesis of cardiovascular, property of Hp is its capacity to bind as myocardial infarction in individ- neurological, infectious, and inflam- free Hb and promote endocytosis via uals with type 2 diabetes (134,136). matory conditions, it would be the CD163 scavenger receptor and These studies and others show that beneficial to patients to have a diag- intracellular degradation of the Hp- Hp2 patients can have as much as a nostic tool that can quickly identify Hb complex (9,37,147). In this pro- five times greater coronary disease risk Hp genotype so proper therapy can cess, Hp can reduce the loss of free and susceptibility to CVD compared be implemented. For example, Hp2-2 Hb through glomerular filtration to patients with the Hp1-1 genotype. is found in ~36% of the population. and promote the recycling of iron. In addition to cardiovascular risk For people with this genotype, at least In addition to its role in clearance, and complications, Hp genotype 10 studies examining nearly 175,000 Hp has a protective function in that also correlates to increased risk for patients collectively have sought to heme and iron released from free Hb

VOLUME 34, NUMBER 3, SUMMER 2016 153 FEATURE ARTICLE

are removed from circulation, thereby 7. Jayle MF, Said I, Gillard P. Action of 22. Nagai T, Okazaki T, Yanagisawa Y. haptoglobin on peroxidase catalysis of Analysis of DNA from subjects found to preventing the production of ROS. hemoglobin: new theory on the formation be heterozygous for the haptoglobin-John- In the context of diabetes, the of enzymes. Bull Soc Chim Biol (Paris) son alpha gene. Exp Clin Immunogenet role of Hp can be either protective 1946;28:63–80 [in French] 1997;14:113–117 or pathogenic. Patients with the Hp2 8. Lim SK. Consequences of haemo- 23. Bensi G, Raugei G, Klefenz H, Cortese lysis without haptoglobin. Redox Rep R. Structure and expression of the human allele have a significantly higher risk 2001;6:375–378 haptoglobin . EMBO J 1985;4:119–126 for cardiovascular, neurological, and 9. Ratanasopa K, Chakane S, Ilyas M, 24. Polticelli F, Bocedi A, Minervini G, infectious complications. Of partic- Nantasenamat C, Bulow L. Trapping of Ascenzi P. 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