Haptoglobin Phenotypes Research Articles

The relationship between repeated measurements of HbA1c and risk of coronary events among the common haptoglobin phenotype groups: the Action for Health in Diabetes (Look AHEAD) study

BackgroundIn the ACCORD study, participants with the haptoglobin (Hp) 2–2 phenotype and glycated hemoglobin (HbA1c) ≥ 8.0% had a higher risk of coronary artery disease (CAD) compared to those with HbA1c 7.0–7.9%. However, this association was not observed in participants without the Hp2-2 phenotype. The optimal glycemic target for CAD prevention for the Hp phenotypes remains uncertain and may vary based on demographic and clinical factors.ObjectiveTo investigate how reaching clinically relevant HbA1c targets relates to the risk of CAD in different Hp phenotype groups among a diverse cohort of individuals with T2DM (the Look AHEAD study, HbA1c ≤ 11% at baseline).MethodsCox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA1c (< 6.5%, 6.5–6.9%, and ≥ 8.0% compared to 7.0-7.9%), updated at years 1–4, 6, 8, and 10, and incident CAD in the Hp2-2 (n = 1,587) and non-Hp2-2 (n = 2,944) phenotypes separately. Further pre-specified subgroup analyses by age, sex, history of cardiovascular disease (CVD), race, and diabetes duration were performed in each Hp phenotype group separately.ResultsCompared with HbA1c 7.0-7.9%, having HbA1c < 6.5% was associated with a 29% lower CAD risk among participants with the non-Hp2-2 phenotype (adjusted HR 0.71, 95% CI 0.55–0.90). In subgroup analyses, this association was present in participants with the non-Hp2-2 phenotype who were male (0.60, 0.44–0.83), who did not have a history of CVD (0.65, 0.47–0.90), who were aged ≥ 65 years (0.64, 0.44–0.94), who were White (0.68, 0.51–0.91), or who had diabetes duration > 10 years (0.58, 0.35–0.95). HbA1c ≥ 8.0% was associated with CAD risk only among participants with the Hp2-2 phenotype who had a history of CVD (1.79, 1.00-3.20). No associations were found between the other HbA1c targets and CAD risk when participants with the Hp2-2 phenotype were grouped together or divided into subgroups.ConclusionThe differences in our results compared to our previous findings may be due to variations in the study populations and factors associated with weight loss, making it difficult to draw definitive conclusions. Our current findings should be considered in the context of hypothesis generation, and ideally, will encourage additional research in this field.

Haptoglobin phenotype and levels in type 2 diabetes and effects of fenofibrate.

In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects. In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post-randomization to fenofibrate or placebo. The Hp phenotypes 1-1, 2-1, and 2-2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P < 0.0001) and decreased (median 21%) after 6 weeks fenofibrate in all phenotypes (adjusted mean (95% CI): -0.27 (-0.32, -0.23) mg/mL in Hp 1-1, -0.29 (-0.31, -0.27) mg/mL in Hp 2-1 and -0.05 (-0.07, -0.02) mg/mL in Hp 2-2 (P = 0.005 and P = 0.055 vs Hp 1-1 and Hp 2-1, respectively)). At 2 years post-randomization the Hp levels in the placebo group had returned to baseline, whilst the fenofibrate-group levels remained similar to the 6 week levels. In type 2 diabetes, Hp levels differ by Hp phenotype and are decreased by fenofibrate in all phenotypes, but the effect is diminished in Hp 2-2.

Does the relationship between time-varying achieved HbA1c and risk of coronary events depend on haptoglobin phenotype within the Action for Health in Diabetes (Look AHEAD) study?

Does the relationship between time-varying achieved HbA1c and risk of coronary events depend on haptoglobin phenotype within the Action for Health in Diabetes (Look AHEAD) study?

Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type two diabetes: The Veterans Affairs Diabetes Trial

BackgroundIntensive glycemic control reduced the risk of coronary artery disease (CAD) events among White ACCORD study participants with the haptoglobin (Hp)2-2 phenotype, and not among participants without the Hp2-2 phenotype. It is unknown whether these results persist in a population with more severe diabetes. MethodsHaptoglobin phenotype was measured in 1746 (97 %) samples from the Veterans Affairs Diabetes Trial (VADT) randomized controlled trial. Multivariable-adjusted Cox regression models assessed the effect of intensive therapy on CAD risk among participants with and without the Hp2-2 phenotype separately and when stratified within pre-specified race/ethnicity-based subgroups. Time-varying (achieved) HbA1c data (<7.0 % or ≥8.0 % compared to 7.0–7.9, updated every 3 months) were also analyzed in relation to CAD risk within each phenotype. Results567 (32.5 %) participants had the Hp2-2 phenotype. Compared to standard therapy, intensive glycemic control was not associated with risk of CAD among participants with the non-Hp2-2 or the Hp2-2 phenotype or for any race/ethnicity-based group. Compared to HbA1c of 7.0–7.9 %, having HbA1c <7.0 % was not associated with CAD risk for either phenotype or among any race/ethnicity-based group. Having HbA1c ≥8.0 % was associated with an increased risk of CAD among Hispanic participants without the Hp2-2 phenotype (HR= 3.61, 95 % CI: 1.54–8.41, p-interaction=0.53). ConclusionThe effect of intensive glycemic therapy on CAD events was not dependent on Hp phenotype in the VADT study of veterans with severe diabetes who may represent a population where Hp phenotype information would not be useful for personalizing diabetes management. However, further research is needed to determine if these results are conclusive.

Haptoglobin Phenotype and Intensive Glycemic Control for Coronary Artery Disease Risk Reduction in People With Type 2 Diabetes: The ADVANCE Study.

Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82-1.32) or with (0.84, 0.63-1.14, Pinteraction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, Pinteraction = 0.01). Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.

Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study

BackgroundIntensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes.MethodsHaptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration.Results1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78–1.17) or with (0.89, 0.68–1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups.ConclusionsHp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants.

Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown. Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0-6.5%, 6.6-6.9%, or ≥8.0% compared with 7.0-7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non-Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables. Compared with HbA1c of 7.0-7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03-1.98) and Black (2.86, 1.09-7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99-1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype. Achieving HbA1c >8.0% compared with 7.0-7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.

Clinical utility of inflammatory and genetic biomarkers for cardiovascular disease prevention, categorization, and treatment.

The complex interplay of increased atherogenic lipoproteins, inflammation, and immune activation hallmarks the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Atherosclerotic cardiovascular disease remains a leading cause of death, yet risk estimator tools lack comprehensiveness for genetic/inflammatory biomarkers associated with ASCVD. Unexplained ASCVD risk necessitates a better understanding of primary, secondary, and tertiary prevention variables. This article discusses the clinical utility of genetic and inflammatory biomarkers for ASCVD risk prediction, management, treatment, and recategorization into primary, secondary, and tertiary prevention. Furthermore, nurse practitioners (NPs) should use a ternary prevention classification system instead of the current binary system to mitigate risk in the large group of patients with subclinical ASCVD. High-sensitivity C-reactive protein (hs-CRP)-linearly associated with ASCVD-and lipoprotein-associated phospholipase-A 2 (Lp-PLA 2 ) and myeloperoxidase (MPO), both associated with plaque vulnerability/rupture, are inflammatory biomarkers. Elevated hs-CRP, MPO, and Lp-PLA 2 treatment requires addressing root causes of elevation (e.g., obesity, insulin resistance, tobacco use, gingival disease, and chronic autoimmune/infectious conditions). In addition, haptoglobin (Hp) phenotype determines the antioxidant potential of Hp. Haptoglobin phenotype, a root cause of ASCVD, is a one-time test. Individuals with Hp 2-2 should adopt a gluten-free diet to reduce endothelial and intestinal inflammation. Nurse practitioners should use stricter glycemic goals (hemoglobin A1c ≤6.5%) and add daily vitamin E if this group has type 2 diabetes. Genetic/inflammatory biomarkers should be used to better predict ASCVD risk and tailor primary, secondary, and tertiary prevention treatment. Clinical use of these biomarkers reaches beyond the standard of care to reduce residual ASCVD risk.

Association of Haptoglobin Phenotypes with Outcomes in Patients with Spontaneous Intracerebral Hemorrhage.

Object. We aimed to investigate the association of Haptoglobin (Hp) phenotypes with perihematomal edema (PHE) and neurological outcomes after intracerebral hemorrhage (ICH). Methods. This prospective multicenter study enrolled patients that suffered ICH from March 2017 to February 2020. Hp phenotypes were determined using Western blotting; relative α1 intensity was calculated in patients with Hp2-1. A multivariable logistic regression analysis was then conducted to identify risk factors for increased relative PHE at 96 h and 3-month poor outcomes. Results. In total, 120 patients were ultimately enrolled: Hp1-1 (n = 15, 12.5%); Hp2-1 (n = 51, 42.5%); and Hp2-2 (n = 54, 45.0%). Hp phenotype was significantly associated with PHE (p = 0.028). With Hp1-1 as a reference value, Hp2-2 significantly increased the likelihood of increased rPHE (OR = 6.294, 95% CI: 1.283–30.881), while Hp2-1 did not (OR = 2.843, 95% CI: 0.566–14.284). Poor outcomes were found to be closely associated with hematoma volume at admission (OR = 1.057, 95% CI: 1.015–1.101) and surgical treatment (OR = 5.340, 95% CI: 1.665–17.122) but not Hp phenotypes (p = 0.190). Further, a high level of relative α1 intensity was identified to be significantly associated with decreased rPHE (OR = 0.020, 95% CI: 0.001–0.358). However, the relative α1 intensity was not associated with poor outcomes (OR = 0.057, 95% CI: 0.001–11.790). Conclusions: ICH patients with Hp2-2 exhibited a higher likelihood of increased rPHE than those with Hp1-1. Higher relative α1 intensities were identified to be closely associated with rPHE in patients with Hp2-1.

MO983: Effect of Haptoglobin Gene Polymorphism On Covid-19 Severity in Kidney Transplant Recipients

BACKGROUND AND AIMSThe SARS-CoV-2 pandemic has become one of the most serious health problems globally. Covid-19 poses a serious life-threatening risk, especially for immunocompromised patients such as kidney transplant recipients. However, the reason why some transplant recipients are asymptomatic while others are severely ill is still not clear. Genetic variation might affect the outcome and mortality of Covid-19 infection. Haptoglobin (Hp) is a plasma protein with antioxidant, immunomodulatory properties and has an important biological function in the host defense responses to infection and inflammation [1]. In humans, Hp is characterized by a molecular heterogeneity with three main genotypes/phenotypes: Hp1-1, Hp2-1, and Hp2-2 [2, 3]. This polymorphism might have important biological consequences in various bacterial and viral infections [3, 4]. In the present study, we aimed to evaluate whether haptoglobin gene polymorphisms effect Covid-19’s severity in kidney transplant patients.METHODAbout 229 renal transplant recipients were evaluated in retrospective fashion. Patients with a history of Covid-19 infection (n:62) were included in the study. We investigated the relation between Hp phenotypes (Hp 1–1, Hp 1–2, Hp 2–2) and Covid-19 disease severity.RESULTSBaseline characteristics, laboratory and health parameters were similar between Hp 1–1, Hp 1–2 and Hp 2–2 groups. We found that Hp2-2 phenotype was a significant predictor of disease severity in renal transplant recipients with Covid-19 (p:0013). Hp 2–2 phenotype was significantly associated with longer hospitalizations and intensive care unit admissions (p:0012 and p:0032).CONCLUSION Renal transplant recipients with the Hp 2–2 phenotype might have worse outcomes with Covid-19. It has been suggested that the Hp2-2 phenotype predisposes to greater oxidative stress and more pronounced viral replication [5]. Thus, the HP 1–1 protein has been described superior antioxidant and anti-inflammatory properties compared with the other two genotypes. This difference and geographic variation in haptoglobin phenotypes may be one of the factors contributing to the geographical variation in Covid-19 disease severity and mortality. Hp phenotype may be useful in the risk stratification algorithm and management of Covid-19. Studies involving more patients will be welcome to enlighten Hp genes effect on this subject.Table 1.Clinical characteristics of renal transplant recipients with Covıd-19All patients (n = 62)Hp 1–1 (n = 8)Hp 1–2 (n = 28)Hp 2–2 (n = 26)P-value Hospitalization days, mean (SD) 5 2 ± 6.52.5 ± 3.12.4 ± 4.39.1 ± 7.3 0.012 Covid pneumonia, n (%) 37 (59.7)5 (62.5)13 (46.4)19 (73.1)0.135 Hypoxia, n (%) 28 (45.2)3 (37.5)7 (25)18 (69.2) 0.004 Tachypnea, n (%) 27 (43,5)4 (50)5 (17.9)18 (69.2) 0.001 Hypotension, n (%) 17 (27,4)2 (25)4 (14.3)11 (42.3)0.069 Tromboemboly, n (%) 3 (4,8)0 (0)0 (0)3 (11.5)0.113 HD/CRRT, n (%) 10 (16,4)0 (0)4 (14.8)6 (23.1)0.292 NIMV, n (%) 17 (27,4)1 (12.5)4 (14.3)12 (46.2) 0.019 Intubation, n (%) 15 (24,2)1 (12.5)4 (14.3)10 (38.5)0.083 İntensive care admission, n (%) 16 (25.8)1 (12.5)3 (10.7)12 (46.2) 0.032 COVID severity, n (%) 0.013 MildModerateSevereCritic 24 (38.7)12 (19.4)11 (17.7)15 (24.2)3 (37.5)2 (25)2 (25)1 (12.5)16 (57.1)7 (25)1 (3.6)4 (14.3)5 (19.2)3 (11.5)8 (30.8)10 (38.5) COVID-related death, n (%) 15 (24.2)1 (12.5)4 (14.3)10 (38.5)0.083

Efficacy Assessment and Mechanism Exploration of Haptoglobin Phenotyping and Peptide Supplementation Strategy for Restenosis

Restenosis is a common complication after balloon angioplasty, and the major mechanism is associated with abnormal proliferation, migration and cellular inflammation of vascular smooth muscle cells. However, its therapeutic diagnosis and treatment as well as the fundamental molecular mechanisms have not been fully established. Different haptoglobin (Hp) phenotypes have been clinically confirmed to be related to the incidence of restenosis, and various Hp subunits have also been found to have a variety of cellular activities, which have the potential to inhibit restenosis. Previous studies have shown that patients with Hp 1‐1 phenotype have the least incidence of restenosis. Therefore, the main axis of this study is to evaluate the efficacies and safeties of the Hp subunits as protein drugs for preventing restenosis, as well as exploring their possible regulatory mechanisms. We have constructed the expression vectors of different Hp subunits to understand the regulatory activities of these subunits on critical signaling pathways. Rat carotid artery balloon‐injury model was used to evaluate the efficacies, additive effects, and possible toxicities of potential Hp subunit on preventing restenosis. The outcomes of this project will help us to understand the feasibility, efficacy and safety of the Hp subunit as protein drugs for preventing vascular restenosis.

T284 Haptoglobin phenotype 2-2 is involved in oxidative stress

T284 Haptoglobin phenotype 2-2 is involved in oxidative stress

Association of Haptoglobin Phenotype With Neurological and Cognitive Outcomes in Patients With Subarachnoid Hemorrhage.

BackgroundTo assess the association of haptoglobin (Hp) phenotype with neurological and cognitive outcomes in a large cohort of patients with subarachnoid hemorrhage (SAH).MethodsThis prospective multicenter study enrolled patients with aneurysmal SAH between May 2015 and September 2020. The Hp phenotype was confirmed via Western blots. The relative intensities of α1 in individuals carrying Hp2-1 were compared with those of albumin. Multivariable logistic and Cox proportional-hazard regression analyses were used to identify the risk factors for 6-month and long-term outcomes, respectively.ResultsA total of 336 patients including the phenotypes Hp1-1 (n = 31, 9.2%), Hp2-1 (n = 126, 37.5%), and Hp2-2 (n = 179, 53.3%) were analyzed. The Hp phenotype was closely associated with 6-month outcome (p = 0.001) and cognitive function (p = 0.013), and long-term outcome (p = 0.002) and cognitive function (p < 0.001). Compared with Hp1-1 as the reference value, Hp2-2 significantly increased the risk of 6-month poor outcome (OR: 7.868, 95% CI: 1.764–35.093) and cognitive impairment (OR: 8.056, 95% CI: 1.020–63.616), and long-term poor outcome (HR: 5.802, 95% CI: 1.795–18.754) and cognitive impairment (HR: 7.434, 95% CI: 2.264–24.409). Long-term cognitive impairment based on the Hp phenotype was significantly higher in patients under 65 years of age (p < 0.001) and female gender (p < 0.001). A lower relative α1/albumin intensity (OR: 0.010, 95% CI: 0.000–0.522) was associated with poor outcome at 6 months but not cognitive impairment in patients with SAH expressing Hp2-1.ConclusionHp2-2 increased the risk of poor neurological outcomes and cognitive impairment compared with Hp1-1. For Hp2-1, higher relative α1 intensities were related to 6-month favorable outcomes.

Rapid Evaluation of the Extent of Haptoglobin Glycosylation Using Orthogonal Intact-Mass MS Approaches and Multivariate Analysis.

Intact-mass measurements are becoming increasingly popular in mass spectrometry (MS) based protein characterization, as they allow the entire complement of proteoforms to be evaluated within a relatively short time. However, applications of this approach are currently limited to systems exhibiting relatively modest degrees of structural diversity, as the high extent of heterogeneity frequently prevents straightforward MS measurements. Incorporation of limited charge reduction into electrospray ionization (ESI) MS is an elegant way to obtain meaningful information on most heterogeneous systems, yielding not only the average mass of the protein but also the mass range populated by the entire complement of proteoforms. Application of this approach to characterization of two different phenotypes of haptoglobin (1-1 and 2-1) provides evidence of a significant difference in their extent of glycosylation (with the glycan load of phenotype 2-1 being notably lighter) despite a significant overlap of their ionic signals. More detailed characterization of their glycosylation patterns is enabled by the recently introduced technique of cross-path reactive chromatography (XP-RC) with online MS detection, which combines chromatographic separation with in-line reduction of disulfide bonds to generate metastable haptoglobin subunits. Application of XP-RC to both haptoglobin phenotypes confirms that no modifications are present within their light chains and provides a wealth of information on glycosylation patterns of the heavy chains. N-Glycosylation patterns of both haptoglobin phenotypes were found to be consistent with bi- and triantennary structures of complex type that exhibit significant level of fucosylation and sialylation. However, multivariate analysis of haptoglobin 1-1 reveals higher number of the triantennary structures, in comparison to haptoglobin 2-1, as well as a higher extent of fucosylation. The glycosylation patterns deduced from the XP-RC/MS measurements are in agreement with the conclusions of the intact-mass analysis supplemented by limited charge reduction, suggesting that the latter technique can be employed in situations when fast assessment of protein heterogeneity is needed (e.g., process analytical technology applications).

Relationship of Haptoglobin Phenotypes With Sarcopaenia in Patients With Congestive Heart Failure

Systemic inflammation in patients with chronic heart failure (CHF) contributes to age-related muscle loss or sarcopaenia. However, the relationship of plasma haptoglobin (Hp), an acute-phase reactant, with muscle and physical health in CHF is unknown. This study investigated the associations of plasma haptoglobin levels and phenotypes with handgrip strength (HGS), appendicular skeletal muscle index (ASMI) and physical capacity in healthy controls (n=67) and CHF patients (n=61) aged 55-73 years. Patients with CHF had higher plasma Hp levels and higher proportions of Hp2-2 phenotype when compared with healthy controls. Plasma Hp2-1 and Hp2-2 levels were negatively associated with HGS and ASMI in healthy controls and CHF (both p<0.05). A negative association of plasma Hp2-2 with gait speed and plasma Hp2-1 with daily steps count was also found in CHF (p<0.05). Patients with Hp2 phenotype showed higher expressions of inflammation and oxidative stress markers, as well as low scores on quality of life parameters. Circulating Hp may be a valuable biomarker for assessing muscle health and physical capacity in CHF.

Does Haptoglobin Phenotype Impact Infection Mortality?

Introduction: The physiological status of a subject and the pathophysiology in some diseases might be under the influence of haptoglobin phenotype. The objective of this work was to determine the relationship between mortality from HIV/AIDS infection and haptoglobin phenotype in a black population in Côte d’Ivoire. Methods: The study was conducted from a retrospective panel of 933 sera/plasma from the previous workup of the ANRS 12136 TEMPRANO trial at month 0 of patients in deferred-ART arms. For each subject, we determined the serum haptoglobin concentration, haptoglobin phenotype, and other variables from patient files from the TEMPRANO trial database. Statistical tests used were Chi-2, Fischer, and Kruskal-Wallis tests for non-gaussian distribution. We used the Kaplan-Meier method for survival analysis. Results: The distributions of the haptoglobin phenotypes were 32.3% for Hp 1-1, 39.5% for Hp 2-1 and 27.2% for Hp 2-2. The blood haptoglobin concentration seemed to be associated with haptoglobin phenotypes (p-value > 5%). The survival rate at M30 and for an extended follow-up up to 6 years was independent of haptoglobin phenotype (p-value > 5%). Besides, the haptoglobin phenotypes do not appear to be associated with CD4+ T-cell count and with hemoglobin concentration. Conclusion: Haptoglobin phenotype seems to not impact the mortality of HIV/AIDS infection. However, given the antioxidant and immunomodulatory properties of some haptoglobin phenotypes, it would be relevant to seek out possible confounding factors indirectly associated with haptoglobin phenotypes and clinical or biological infection variables.

Distribution of Haptoglobin Phenotypes among Patients with HIV/AIDS, Hepatitis B, Liver Cirrhosis and Chronic Renal Failure in Sudan

Haptoglobin (Hp) is a plasma α2-glycoprotein that binds free haemoglobin and is thought to have a role in the immune pathway of different pathologies depending on its phenotype. A total of 497 Sudanese patients with viral infections and non-infectious diseases were typed for haptoglobin phenotypes, in this study, using the polyacrylamide non-reducing gel electrophoresis separation method to determine possible associations between haptoglobin phenotypes Hp1-1, Hp2-1 and Hp2-2. Viral infections included human immunodeficiency virus (HIV) (n= 129) and hepatitis B (HBV) (n=171). The non-infectious diseases were: liver cirrhosis (LC) (n=68) and chronic renal failure (CRF) (n= 129). Healthy controls (n= 65) were also typed. Each disease sample was compared with the control. Expected percentages of each of the three phenotypes in Sudan estimated using SPSS were between 51.38-51.49% for Hp1-1, 36.71-36.81% for Hp2-1 and 11.76-11.91% for Hp2-2. Hp1-1 was found the most significantly prevalent among patients with LC (P≤0.05). Patients with HIV/AIDS and HBV showed the same distribution of haptoglobin phenotypes as the healthy control (i.e. a majority of Hp2-1); whereas the highest percentage of patients with Hp2-2 were those with CRF (≥23%) although not significantly different from the control. Using Hardy-Weinberg equilibrium (HWE) as a null model, hp1allele frequency was calculated to be 0.69 and hp2allele frequency was 0.31 in Sudan. The healthy control, LC and CRF sampled populations were significantly deviated from HWE (P=0.05). In this study, we found that Hp1-1 has a significant association with LC. HIV/AIDS and HBV showed the same distribution of phenotypes as control and the highest percentage of patients with Hp2-2 were those with CRF. hp1and hp2allele frequencies were 0.69 and 0.31 in Sudan.

Haptoglobin as a Biomarker.

—Haptoglobin (Hp) is a glycoprotein that binds free hemoglobin (Hb) in plasma and plays a critical role in tissue protection and prevention of oxidative damage. Besides, it has some regulatory functions. Haptoglobin is an acute-phase protein, its concentration in plasma changes in pathology, and the test for its concentration is part of normal clinical practice. Haptoglobin is a conservative protein synthesized mainly in the liver and lungs and is the subject of research as a potential biomarker of many diseases, including various forms of malignant neoplasms. Haptoglobin has several unique biophysical characteristics. The human Нр gene is polymorphic, has three structural alleles that control the synthesis of three major phenotypes of haptoglobin: homozygous Нр1-1 and Нр2-2, and heterozygous Нр2-1, determined by a combination of allelic variants that are inherited. Numerous studies indicate that the phenotype of haptoglobin can be used to judge the individual predisposition of a person to various diseases. In addition, Hp undergoes various post-translational modifications (PTMs). These are structural transformations (removal of the signal peptide, cutting off the Pre-Hp precursor molecule into two subunits, α and β, limited proteolysis of α-chains, formation of disulfide bonds, multimerization), as well as chemical modifications of α-chains and glycosylation of the β-chain. Glycosylation of the β-chain of haptoglobin at four Asn sites is the most important variable PTM that regulates the structure and function of the glycoprotein. The study of modified oligosaccharides of the β-chain of Hp has become the main direction in the study of pathological processes, including malignant neoplasms. These characteristics indicate the possibility of the existence of Hp in the form of a multitude of proteoforms, probably performing different functions. This review is devoted to the description of the structural and functional diversity and the potential use of Hp as a biomarker of various pathologies.

Evaluation of Haptoglobin and Its Proteoforms as Glioblastoma Markers.

Haptoglobin (Hp) is a blood plasma glycoprotein that plays a critical role in tissue protection and the prevention of oxidative damage. Haptoglobin is an acute-phase protein, its concentration in plasma changes in pathology, and the test for its concentration is part of normal clinical practice. Haptoglobin is a conservative protein and is the subject of research as a potential biomarker of many diseases, including malignant neoplasms. The Human Hp gene is polymorphic and controls the synthesis of three major phenotypes—homozygous Hp1-1 and Hp2-2, and heterozygous Hp2-1, determined by a combination of allelic variants that are inherited. Numerous studies indicate that the phenotype of haptoglobin can be used to judge the individual’s predisposition to various diseases. In addition, Hp undergoes various post-translational modifications (PTMs). Glioblastoma multiform (GBM) is the most malignant primary brain tumor. In our study, we have analyzed the state of Hp proteoforms in plasma and cells using 1D (SDS-PAGE) and 2D electrophoresis (2DE) with the following mass spectrometry (LC ES-MS/MS) or Western blotting. We found that the levels of α2- and β-chain proteoforms are up-regulated in the plasma of GBM patients. An unprocessed form of Hp2-2 (PreHp2-2, zonulin) with unusual biophysical parameters (pI/Mw) was also detected in the plasma of GBM patients and glioblastoma cells. Altogether, this data shows the possibility to use proteoforms of haptoglobin as a potential GBM-specific plasma biomarker.

Haptoglobin as a biomarker

Haptoglobin (Hp) is a blood plasma glycoprotein that binds free hemoglobin (Hb) and plays a critical role in tissue protection and the prevention of oxidative damage. In addition, it has a number of regulatory functions. Haptoglobin is an acute phase protein, its concentration in plasma changes in pathology, and the test for its concentration is part of normal clinical practice. Haptoglobin is a conservative protein synthesized mainly in the liver and lungs and is the subject of research as a potential biomarker of many diseases, including various forms of malignant neoplasms. Haptoglobin has several unique biophysical characteristics. Only in humans, the Hp gene is polymorphic, has three structural alleles that control the synthesis of three major phenotypes of Hp, homozygous Hp1-1 and Hp2-2, and heterozygous Hp2-1, determined by a combination of allelic variants that are inherited. Numerous studies indicate that the phenotype of haptoglobin can be used to judge the individual's predisposition to various diseases. In addition, Hp undergoes various post-translational modifications (PTMs). These are structural transformations (removal of the signal peptide, cutting of the Pre-Hp precursor molecule into two subunits, α and β, limited proteolysis of α-chains, formation of disulfide bonds, multimerization), as well as chemical modifications of α-chains and glycosylation of the β-chain. Glycosylation of the β-chain of haptoglobin at four Asn sites is the most important variable PTM that regulates the structure and function of the glycoprotein. The study of modified oligosaccharides of the Hp β-chain has become the main direction in the study of pathological processes, including malignant neoplasms. Many studies are focused on the identification of PTM and changes in the level of the α2-chain of this protein in pathology. These characteristics of Hp indicate the possibility of the existence of this protein as different proteoforms, probably with different functions. This review is devoted to the description of the structural and functional diversity of Hp and its potential use as a biomarker of various pathologies.