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Intestinal permeability has been related to colorectal cancer (CRC) development. Zonulin, a protein able to regulate tight junction function and intestinal permeability, emerges as a promising marker to elucidate the contribution of bacterial translocation in CRC. An Italian case-control study included 77 CRC cases, 72 intestinal adenoma and 76 healthy controls (for a total of 148 tumor-free subjects), aged 20-85. Serum zonulin levels were quantified by ELISA kit and blood 16S rRNA gene copies by DNA extraction and polymerase chain reaction. We applied logistic regression models adjusted for center, sex, age and education. There was a positive association between zonulin and CRC risk. The odds ratio (OR) of CRC for the highest versus lowest tertile of zonulin as compared to tumor-free subjects was 2.36 (95% confidence interval, 1.14-4.86). The ORs were similar in colon and rectal cancers. The OR of colon cancer for the highest versus lowest levels of both zonulin and 16S rRNA gene copies was 4.55.Circulating levels of zonulin were higher in CRC patients compared to tumor-free controls supporting the hypothesis of an interplay of gut barrier dysfunction and bacterial translocation in colorectal carcinogenesis. Zonulin may interact with 16S rRNA gene copies and serve as a further biomarker in the evaluation of CRC diagnosis., Competing Interests: Declarations Ethics approval and consent to participate The study was conducted according to the guidelines of the Declaration of Helsinki, and ap-proved by the Ethics Committees of ASST Grande Ospedale Metropolitano Niguarda (No. 477–112016; November 25, 2016) and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (No. 742–2017; December 14, 2017). Written informed consent was obtained from all subjects involved in the study. Consent for publication All authors consent to the publication of the present version of the manuscript. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Importance: Individuals with psychiatric disorders have been reported to have elevated levels of inflammatory biomarkers, and prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk., Objective: To assess the associations between inflammation biomarkers and subsequent psychiatric disorders risk., Design, Setting, and Participants: This was a prospective cohort study including individuals from the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort, with no prior psychiatric diagnoses and having a measurement of at least 1 inflammatory biomarker. Data from the UK Biobank were used for validation. Longitudinal trajectories of studied biomarkers were visualized before diagnosis of psychiatric disorders in the AMORIS cohort via a nested case-control study. In addition, genetic correlation and mendelian randomization (MR) analyses were conducted to determine the genetic overlap and causality of the studied associations using publicly available GWAS summary statistics., Exposures: Inflammatory biomarkers, eg, leukocytes, haptoglobin, immunoglobulin G (IgG), C-reactive protein (CRP), platelets, or albumin., Main Outcomes and Measures: Any psychiatric disorder or specific psychiatric disorder (ie, depression, anxiety, and stress-related disorders) was identified through the International Statistical Classification of Diseases, Eighth, Ninth, and Tenth Revision codes., Results: Among the 585 279 individuals (mean [SD] age, 45.5 [14.9] years; 306 784 male [52.4%]) in the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11; 95% CI, 1.09-1.14), haptoglobin (HR, 1.13; 95% CI, 1.12-1.14), or CRP (HR, 1.02; 95% CI, 1.00-1.04) had an elevated associated risk of any psychiatric disorders. In contrast, we found an inverse association for IgG level (HR, 0.92; 95% CI, 0.89-0.94). The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank (n = 485 620). Analyses of trajectories revealed that individuals with psychiatric disorders had higher levels of leukocytes and haptoglobin and a lower level of IgG than their controls up to 30 years before the diagnosis. The MR analysis suggested a possible causal relationship between leukocytes and depression., Conclusions and Relevance: In this cohort study, inflammatory biomarkers including leukocytes, haptoglobin, CRP, and IgG were associated with a subsequent risk of psychiatric disorders, and thus might be used for high-risk population identification. The possible causal link between leukocytes and depression supports the crucial role of inflammation in the development of psychiatric disorders.

Background: Vitamin E, an essential micronutrient with antioxidant potential, can dramatically reduce the cardiovascular risk in individuals with haptoglobin (Hp) 2-2 genotype diabetes; however, the underlying mechanism remains unclear. Objective: The objective of this study is to evaluate the effect of vitamin E supplementation on high-density lipoprotein (HDL) levels and function in individuals with diabetes stratified by Hp genotype. Methods: All relevant studies published up to May 2023 were systematically reviewed using PubMed, Cochrane Library, Web of Science, Chinese Wanfang, China Science and Technology Journal, and Chinese National Knowledge Infrastructure databases. Randomized controlled trials that evaluated the effects of vitamin E supplementation on HDL levels were included. The outcomes assessed were changes in HDL concentrations, cholesterol efflux, and HDL-associated lipid peroxides. Results: In total, 163 publications were selected. Based on inclusion and exclusion selection and quality assessment, five studies with 463 participants were included. Vitamin E supplementation did not exert any effect on HDL levels in individuals with diabetes with any Hp genotype. Three of the five studies revealed that vitamin E improved cholesterol efflux and HDL lipid peroxides in individuals with Hp2-2 diabetes but did not positively impact HDL function in Hp1 carriers. Conclusions: Although vitamin E supplementation did not significantly impact HDL levels in individuals with diabetes of any Hp genotype, it may improve HDL function in individuals with Hp2-2 diabetes. These findings indicate a pharmacogenetic interaction between vitamin E and the Hp genotype on HDL function. Moreover, vitamin E supplementation may be an effective strategy for specific individuals with diabetes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Pan-pan Zheng et al.)

Background: In the ACCORD study, participants with the haptoglobin (Hp) 2-2 phenotype and glycated hemoglobin (HbA 1c ) ≥ 8.0% had a higher risk of coronary artery disease (CAD) compared to those with HbA 1c 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., Objective: To investigate how reaching clinically relevant HbA 1c targets relates to the risk of CAD in different Hp phenotype groups among a diverse cohort of individuals with T2DM (the Look AHEAD study, HbA 1c  ≤ 11% at baseline)., Methods: Cox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA 1c (< 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., Results: Compared with HbA 1c 7.0-7.9%, having HbA 1c  < 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). HbA 1c  ≥ 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 HbA 1c targets and CAD risk when participants with the Hp2-2 phenotype were grouped together or divided into subgroups., Conclusion: The 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., (© 2024. The Author(s).)

HCC is a malignancy characterized by high incidence and mortality rates. Traditional classifications of HCC primarily rely on tumor morphology, phenotype, and multicellular molecular levels, which may not accurately capture the cellular heterogeneity within the tumor. This study integrates scRNA-seq and bulk RNA-seq to spotlight HP as a critical gene within a subgroup of HCC malignant cells. HP is highly expressed in HCC malignant cells and lowly expressed in T cells. Within malignant cells, elevated HP expression interacts with C3, promoting Th1-type responses via the C3/C3AR1 axis. In T cells, down-regulating HP expression favors the expression of Th1 cell-associated marker genes, potentially enhancing Th1-type responses. Consequently, we developed a "HP-promoted Th1 response reclassification" gene set, correlating higher activity scores with improved survival rates in HCC patients. Additionally, four predictive models for neoadjuvant treatment based on HP and C3 expression were established: 1) Low HP and C3 expression with high Th2 cell infiltration; 2) High HP and low C3 expression with high Th2 cell infiltration; 3) High HP and C3 expression with high Th1 cell infiltration; 4) Low HP and high C3 expression with high Th1 cell infiltration. In conclusion, the HP gene selected from the HCC malignant cell subgroup (Malignant&#95;Sub 6) might serve as a potential ally against the tumor by promoting Th1-type immune responses. The establishment of the "HP-promoted Th1 response reclassification" gene set offers predictive insights for HCC patient survival prognosis and neoadjuvant treatment efficacy, providing directions for clinical treatments., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. All authors read the journal's policy on disclosure of potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To explore whether the intestinal damage of yak colibacillosis resulted from the regulation of Zonulin expression by its pathogenic bacteria, the overexpression and interference plasmids of Zonulin were designed and cultured in Tranwell after cell transfection. Then qRT-PCR and Western blot were used to detect the results of cell transfection, 200 mL 1×105 CFU/mL E.coli O78 was added for 4 hours, transmembrane resistance was measured by transmembrane resistance meter, FD4 fluorescence concentration in the lower chamber was detected by enzyme labeling instrument, bacterial translocation was measured by CFU counting method, and epithelial mucin (MUC1, MUC2) and tight junction protein (FABP2, Occludin, ZO-1) were detected by qRT-PCR., Results: The Zonulin gene overexpression and knockout cell lines were successfully constructed, the TEER value of the barrier of Zonulin overexpression cell lines began to decrease at 1 h after the addition of E.coli O78 and reached the lowest value at 4 h, and the TEER value of Zonulin interference cell lines decreased within 1-4 h after the addition of E.coli O78. At 4 h, the FD4 passing capacity of Zonulin overexpression cell lines was significantly higher than that of interfering cell lines, reaching twice as much as siRNA-1. The amount of bacterial translocation in overexpressed cell lines increased rapidly within 1-4 h, and the concentration of E.coli in the lower chamber was significantly higher than that in the siRNA-1 group at 4 h, but there was no significant change in the siRNA-1 group in the 1-4 h. There was no significant change in the mRNA level of MUC1 in Zonulin overexpression and interference cell lines after the addition of E.coli O78. In the overexpression group, the mRNA levels of MUC2, Occludin, and ZO-1 were significantly decreased, and the mRNA level of FABP2 was increased considerably. These results suggest stimulate epithelial cells to secrete Zonulin protein. Many Zonulin proteins regulate the opening of tight junction structures, reduce the transmembrane resistance of the cell barrier, and improve the permeability of the cell barrier and the amount of bacterial translocation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ren, Shi, Chang, Zhang, Wang, Liu, Sang, Dong and Wu.)

Background: Influenza is an acute respiratory disease posing significant harm to human health. Early prediction and intervention in patients at risk of developing severe influenza can significantly decrease mortality., Method: A comprehensive analysis of 146 patients with influenza was conducted using the Gene Expression Omnibus (GEO) database. We assessed the relationship between severe influenza and patients' clinical information and molecular characteristics. First, the variables of differentially expressed genes were selected using R software. Least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis were performed to investigate the association between clinical information and molecular characteristics and severe influenza. A nomogram was developed to predict the presence of severe influenza. At the same time, the concordance index (C-index) is adopted area under the receiver operating characteristic (ROC), area under the curve (AUC), decision curve analysis (DCA), and calibration curve to evaluate the predictive ability of the model and its clinical application., Results: Severe influenza was identified in 47 of 146 patients (32.20%) and was significantly related to age and duration of illness. Multivariate logistic regression demonstrated significant correlations between severe influenza and myloperoxidase (MPO) level, haptoglobin (HP) level, and duration of illness. A nomogram was formulated based on MPO level, HP level, and duration of illness. This model produced a C-index of 0.904 and AUC of 0.904., Conclusions: A nomogram based on the expression levels of MPO, HP, and duration of illness is an efficient model for the early identification of patients with severe influenza. These results will be useful in guiding prevention and treatment for severe influenza disease., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Observational studies have suggested an association between plasma haptoglobin and multiple sclerosis (MS). Haptoglobin plays an important role in the pathogenesis of MS. However, whether it has a causal effect on MS remains unknown., Methods: We here used a two-sample bidirectional Mendelian randomization (MR) method to investigate the causality between haptoglobin and MS. Genetic variants associated with plasma haptoglobin from two independent genome wide association studies (GWASs) (used as the discovery and replication datasets, respectively) were applied as the exposure. Their causal effects on summary statistics of GWASs of MS and disease severity were evaluated using the inverse-variance weighted (IVW) approach as the main analysis component., Results: We found in both discovery and replication dataset that plasma haptoglobin was causally positively associated with the risk of MS (discovery: OR: 1.063, 95% CI: 1.022-1.106, P = 0.002; replication: OR: 1.041, 95% CI: 1.005-1.078, P = 0.026), but it was not associated with MS severity (discovery: OR: 1.017, 95% CI: 0.993-1.042, P = 0.168; replication: OR: 1.011, 95% CI: 0.987-1.036, P = 0.373). Besides, we did not detect any significant results in the reverse causation analysis., Conclusions: Our study provides evidence for the causal effects of plasma haptoglobin on the risk of MS., Competing Interests: Declarations Conflict of interest The authors have no conflicts of interest. Ethical approval and informed consent All data used in this study were available in the original GWAS studies, and patient consent and ethical approval were obtained in the corresponding institution., (© 2024. Fondazione Società Italiana di Neurologia.)

Haptoglobin is a plasma protein of mammals that plays a crucial role in vascular homeostasis by binding free haemoglobin released from ruptured red blood cells. Trypanosoma brucei can exploit this by internalising haptoglobin-haemoglobin complex to acquire host haem. Here, we investigated the impact of haptoglobin deficiency (Hp-/-) on T. brucei brucei infection and the parasite´s capacity to internalise haemoglobin in a Hp-/- mouse model. The infected Hp-/- mice exhibited normal disease progression, with minimal weight loss and no apparent organ pathology, similarly to control mice. While the proteomic profile of mouse sera significantly changed in response to T. b. brucei , no differences in the infection response markers of blood plasma between Hp-/- and control Black mice were observed. Similarly, very few quantitative differences were observed between the proteomes of parasites harvested from Hp-/- and Black mice, including both endogenous proteins and internalised host proteins. While haptoglobin was indeed absent from parasites isolated from Hp-/-mice, haemoglobin peptides were unexpectedly detected in parasites from both Hp-/- and Black mice. Combined, the data support the dispensability of haptoglobin for haemoglobin internalisation by T. b. brucei during infection in mice. Since the trypanosomes knock-outs for their haptoglobin-haemoglobin receptor (HpHbR) internalised significantly less haemoglobin from Hp-/- mice compared to those isolated from Black mice, it suggests that T. b. brucei employs also an HpHbR-independent haptoglobin-mediated mode for haemoglobin internalisation. Our study reveals a so-far hidden flexibility of haemoglobin acquisition by T. b. brucei and offers novel insights into alternative haemoglobin uptake pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Horáková, Vrbacký, Tesařová, Stříbrná, Pilný, Vavrušková, Vancová, Sobotka, Lukeš and Perner.)

Background: This study aimed to assess whether the Haptoglobin (Hp) genotype influences the relationship between hemoglobin (Hb) levels and the development of gestational diabetes mellitus (GDM). Additionally, it sought to evaluate the interaction and joint association of Hb levels and Hp genotype with GDM risk., Methods: This retrospective study involved 358 women with GDM and 1324 women with normal glucose tolerance (NGT). Peripheral blood leukocytes were collected from 360 individuals at 14-16 weeks' gestation for Hp genotyping. GDM was diagnosed between 24-28 weeks' gestation. Interactive moderating effect, joint analysis, and mediation analysis were performed to evaluate the crosslink of Hb levels and Hp genotype with GDM risk., Results: Women who developed GDM had significantly higher Hb levels throughout pregnancy compared to those with NGT. Increase first-trimester Hb concentration was associated with a progressive rise in GDM incidence, glucose levels, glycosylated hemoglobin levels, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) values, cesarean delivery rates, and composite neonatal outcomes. Spline regression showed a significant linear association of GDM incidence with continuous first-trimester Hb level when the latter exceeded 122 g/L. Increased first-trimester Hb concentration was an independent risk factor for GDM development after adjusting for potential confounding factors in both the overall population and a matched case-control group. The Hp2-2 genotype was more prevalent among pregnant women with GDM when first-trimester Hb exceeded 122 g/L. Significant multiplicative and additive interactions were identified between Hb levels and Hp genotype for GDM risk, adjusted for age and pre-pregnancy BMI. The odds ratio (OR) for GDM development increased incrementally when stratified by Hb levels and Hp genotype. Moreover, first-trimester Hb level partially mediated the association between Hp genotype and GDM risk., Conclusion: Increased first-trimester Hb levels were closely associated with the development of GDM and adverse pregnancy outcomes, with this association moderated by the Hp2-2 genotype., (© 2024. The Author(s).)

Haptoglobin (Hp) is a polymorphic protein that was initially described as a hemoglobin (Hb)-binding protein. The major functions of Hp are to scavenge Hb, prevent iron loss, and prevent heme-based oxidation. Hp regulates angiogenesis, nitric oxide homeostasis, immune responses, and prostaglandin synthesis. Genetic polymorphisms in the Hp gene give rise to different phenotypes, including Hp 1-1, Hp 2-1, and Hp 2-2. Extensive research has been conducted to investigate the association between Hp polymorphisms and several medical conditions including cardiovascular disease, inflammatory bowel disease, cancer, transplantation, and hemoglobinopathies. Generally, the Hp 2-2 phenotype is associated with increased disease risk and poor outcomes. Over the years, the Hp 2 allele has spread under genetic pressures. Individuals with the Hp 2-2 phenotype generally exhibit lower levels of CD163 expression in macrophages. The decreased expression of CD163 may be associated with the poor antioxidant capacity in the serum of subjects carrying the Hp 2-2 phenotype. However, the Hp 1-1 phenotype may confer protection in some cases. The Hp1 allele has strong antioxidant, anti-inflammatory, and immunomodulatory properties. It is important to note that the benefits of the Hp1 allele may vary depending on genetic and environmental factors as well as the specific disease or condition under consideration. Therefore, the Hp1 allele may not necessarily confer advantages in all situations, and its effects may be context-dependent. This review highlights the current understanding of the role of Hp polymorphisms in cardiovascular disease, inflammatory bowel disease, cancer, transplantation, hemoglobinopathies, and polyuria.

According to the Assessment of SpondyloArthritis International Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axial spondyloarthritis (axSpA), patients should undergo at least two courses of non-steroidal anti-inflammatory drugs (NSAIDs) therapy. In our study, we enrolled axSpA patients both at onset and in a flare who had already been treated with NSAIDs ineffectively. Subsequently, according to the recommendations, they received modified NSAID treatment as another attempt to the first-line drug therapy and were monitored from there. We aimed to identify risk factors for treatment failure after 4 weeks (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4) especially amongst zonulin and haptoglobin concentrations, and haptoglobin polymorphism. Treatment failure was observed in 71% of patients, and the following variables were contributed for occurrence of this state: higher zonulin levels, ankylosing spondylitis, X-ray sacroiliitis, magnetic resonance imaging sacroiliitis, long duration of symptoms, high BASDAI, and high value of spinal pain intensity on visual analogue scale. In addition, the following positive correlations were found: haptoglobin concentration with C-reactive protein (r = 0.56; p = 0.0004), and erythrocyte sedimentation rate (r = 0.62; p < 0.0001), as well as between zonulin levels and white blood count (r = 0.5; p = 0.0003). The results of the study presented the identified factors related to the standard treatment failure in axSpA, amongst them zonulin levels. They might be applied to point out the patients for whom the search for a more appropriate method of treatment should be considered., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Intensive 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., Methods: Haptoglobin 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., Results: 1590 (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., Conclusions: Hp 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., (© 2024. The Author(s).)

Objective: This study aimed to assess the relative gene expression level of transforming growth factor-β1 (TGFB1) and haptoglobin (HP) in the peripheral blood of prostate cancer (PCa) patients and evaluate their diagnostic ability., Methods: A total of 125 participants were enrolled in the present study. Among them, 75 PCa patients, 25 benign prostatic hyperplasia (BPH) patients, and 25 healthy volunteers served as the control group. The relative TGFB1 and HP gene expression level was quantified using real-time polymerase chain reaction. Further, free and total PSA levels were determined using electrochemiluminescence assays., Results: TGFB1 was significantly over-expressed, whereas HP was significantly downregulated in the peripheral blood of PCa patients compared to BPH and control groups (p-value ranges from 0.034 to <0.001). Moreover, the high expression level of TGFB1 was associated with an increased risk of PCa development with OR=1.412 (95%CI: 1.081-1.869, p= 0.012). TGFB1 and HP relative expression levels had lower diagnostic performance to differentiate PCa from normal and BPH individuals compared to PSA, however, the combination of the tested parameters improved the diagnostic efficacy., Conclusions: TGFB1 and HP relative expression have moderate diagnostic efficacy in discriminating patients with PCa from BPH and healthy subjects. Furthermore, over-expression of TGFB1 may contribute to the pathogenesis of PCa.

Background: Major sickle cell syndromes are the most common hemoglobinopathy in the world. The sickle cell patients are subjected to several factors causing inflammation, and the genetic identification of each individual allows to focus the possibility of allelic variations influence of a specific gene and then the polymorphism. This study aims at determining the distribution of HP gene (OMIM#140100) and their involvement on hematological parameters and the iron profile in the sickle cell patients presenting an inflammation condition during major sickle cell syndromes in Cameroun., Methods: A case-control analytical study has been conducted over a period of 6 months. Cases consisting of sickle cell patients in a situation of inflammation and control of non-inflamed sickle cell patients. The patients presenting major sickle cell syndromes, interned and/or followed at the Hematology Department of the Regional Hospital of Bafoussam and the Central Hospital of Yaoundé have been recruited. HP genotyping was carried out at the Laboratory for Public Health Research Biotechnologies (LAPHER-Biotech) in Yaoundé using allele-specific PCR. Also, inflammatory, hematological parameters and martial assessment were explored by standard methods. Statistical analysis of the data was performed using the statistical tool R version 4.1.1. The comparison of proportions of alleles was made with the chi-square test, and the Wilcoxon test was used to compare the median between different groups using the statistical tool R version 4.1.1., Results: We analyzed the samples of 149 patients. The HP polymorphism describes a significant frequency of the "1F" allele (69.8%) followed by the "2" allele (46.31%). In addition, 80 patients (53.69%), 48 (32.21%), and 21 (14.09%) presented the genotype HP 1-1, HP 2-1, and HP 2-2, respectively. And eighty-one percent (81%) patients with genotype HP 2-2 showed a significant higher relative frequency of thrombocytosis compared with the genotype HP 1-1 and HP 2-1, respectively (51.2% and 68.8%, p = 0.087). The proportion of inflammation in the HP 2-2 group was higher (57.1%) compared with the other groups (respectively 42.5% and 35.4% in the HP 1-1 and HP 2-1 groups). Furthermore, the median CRP was significantly higher in the HP 2-2 group compared with the other groups (p = 0.039). Moreover, the entire population of the HP 2-2 group showed an elevation of ferritin and IL6 unlike the HP 1-1 and HP 2-1 groups., Conclusion: This study demonstrates a higher frequency of genotype HP 1-1 followed by the HP 2-2 genotype in patients with major sickle cell syndromes. However, a larger proportion of patients with genotype HP 2-2 are associated with hematological profile disorders, inflammation, and dysregulation of iron metabolism. Then, the haptoglobin polymorphism contributes to the severity of major sickle cell syndromes., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Rationale: Immune system deregulation, including AAV, is a key event that may potentially evolve into ESRD. Abnormal activation of the cAP is also a cardinal feature of TMA, particularly aHUS. The kidney is the most frequently involved organ, and renal-limited forms of TMA are often encountered in clinical practice. Isolated case reports described the occurrence of renal TMA in AAV patients. Some cases of both de novo and relapses of AAV and/or TMAs after anti-SARS-CoV2 vaccination have been reported. We reported, for the 1st time, a case of patients with new-onset MPA and aHUS occurring 3 weeks after the third dose of mRNA-1273 vaccine anti-SARS-CoV2., Patient Concerns: We present a 67-year-old man, affected by arterial hypertension, reported, after mRNA-1273 vaccine anti-SARS-CoV2, anuria, fatigue, anorexia and nausea. Laboratory data revealed acute renal failure., Diagnosis: Positivity of MPO-ANCA was observed. 7 days after admission, we observed a worsening of anemia and thrombocytopenia with haptoglobin reduction, LDH increase and presence of schistocytes. Plasma levels of ADAMTS-13 were normal. A renal biopsy was performed, and findings were consistent with microscopic polyangiitis, with features of micro-thrombotic glomerulopathy. Genetic tests revealed absence of hybrid genes associated with the increased risk of aHUS., Interventions and Outcomes: We started renal replacement treatment, including hemodialysis, and pulsed methylprednisolone, with no improvement of laboratory parameters. Then, plasma exchange was performed leading to partial haematological response. Only with Eculizumab, a human C5 inhibitor, we observed a normalization of haptoglobin levels and platelets' count. However, three months after discharge, the patient still required hemodialysis., Lessons: To our knowledge we observed the first case aHUS, without genetic predisposition, associated with MPA occurring after the third dose of anti-SARS-CoV2 vaccine. This case report highlights the potential link between anti-SARS-CoV2 vaccine as a trigger of MPA and aHUS. This systematic review offers additional perspectives. It is plausible to hypothesize that the vaccine was the trigger for the development of these 2 diseases.Solid evidence on the mechanisms of interaction between vaccine and immune system, the role of genetic predisposition, and other variables, will shed additional light on the controversial link between anti-SARS-CoV2 vaccine and autoimmunity., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: In Japan, the prevalence of haptoglobin deficiency is approximately 1 in 4000. Haptoglobin-deficient individuals may produce anti-haptoglobin from allo-immunization, leading to serious transfusion reactions. Therefore, implementation of a consistent supply of haptoglobin-deficient fresh frozen plasma is crucial. We developed a novel reagent to facilitate large-scale identification of haptoglobin-deficient individuals as potential donors of plasma products., Materials and Methods: We established mouse monoclonal anti-haptoglobin-producing cell lines (three clones) using the hybridoma method by immunizing mice with the haptoglobin protein. Purified antibodies were conjugated with carboxylate-modified polystyrene latex beads and used for haptoglobin measurements by the latex agglutination method using an automatic analyser (LABOSPECT008). Samples with low protein concentrations were re-examined by enzyme-linked immunosorbent assay to confirm the results. Additionally, the haptoglobin gene was amplified by polymerase chain reaction to confirm the haptoglobin deletion allele (Hp del )., Results: From February to October 2022, 7476 blood donor samples were screened. Two haptoglobin-deficient and 21 low-haptoglobin-expressing individuals were identified. Two haptoglobin-deficient donors were found homozygous for Hp del , and 19 (90%) of the 21 low-haptoglobin-expressing individuals were heterozygous for Hp del , which includes the first reported case of heterozygous Hp del /Hp Johnson ., Conclusion: We developed a new reagent for the detection of haptoglobin deficiency, which is automatable and inexpensive and appears useful for large-scale screening of blood donors., (© 2023 International Society of Blood Transfusion.)

Background: The Haptoglobin ( Hp ) genotypes have been linked to immune diseases and play a significant role in metabolic diseases. This study aimed to analyze the correlation between Hp gene polymorphism and the severity of hepatitis B accompanied by liver steatosis., Methods: A total of 182 with Hepatitis B and concurrent hepatic steatosis were included in the study. Clinical biochemical indices for each participant were recorded. DNA was extracted from peripheral blood leukocytes for globin genotyping. Of these participants, 128 underwent biopsy from which histological data were collected., Results: Subjects with hepatitis B and hepatic steatosis carrying the Hp 2-2 genotype exhibited elevated alanine transaminase (ALT), c-glutamyl transferase (GGT), and aspartate amino transferase (AST) levels. In contrast, high-density lipoprotein (HDL) levels and the copy number of Hepatitis B Virus (HBV)-DNA were significantly reduced in those with the Hp 2-2 genotype ( p < 0.05). Furthermore, individuals processing the Hp 2-2 genotype demonstrated a heightened hepatitis score and advanced fibrosis stage ( p < 0.05). Notably, the Hp 2-2 genotype was independently associated with increased inflammation (odds ratio (OR) = 7.059, p < 0.001) and progressive fibrosis (OR = 3.05, p < 0.022)., Conclusions: The Hp 2-2 genotype is significantly associated with increased severity in cases of hepatitis B with coexisting hepatic steatosis.

Objective: 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., Research Design and Methods: 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., Results: 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., Conclusions: 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., (© 2023 by the American Diabetes Association.)

Significance Statement: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility., Background: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated., Methods: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression., Results: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03)., Conclusions: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility., (Copyright © 2023 by the American Society of Nephrology.)

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening., (© 2023. The Author(s).)

Background: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2., Methods: HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models., Results: The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers., Discussion: The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Haptoglobin (Hp) is a hemoglobin-binding protein that functions as an antioxidant in human plasma. It is reported that glycemic variability (GV) plays a key role in diabetes-related complications associated with impaired glucose metabolism and oxidative stress. Here we aim to investigate whether the effect of GV on diabetic macroangiopathy depends on Hp genotype in type 2 diabetes., Methods: A number of 860 Chinese patients with type 2 diabetes was genotyped and assigned to two Hp subgroups (Hp 2-2 and Hp 1 carriers). Glycemic variability (GV) was assessed by using a retrospective continuous glucose monitoring system for three consecutive days, and it was measured using the glucose coefficient of variation (%CV), which is calculated as the ratio of glucose standard deviation to glucose mean. Clinical features, history of cardiac surgery, and vascular imaging tests were utilized to diagnose macroangiopathy. We evaluated the interaction between Hp genotypes and %CV on diabetic macroangiopathy. Furthermore, serum concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured using an enzyme-linked immunosorbent assay as a biomarker of oxidative stress., Results: Serum 8-OHdG levels were positively correlated with %CV in Hp 1 carriers (r = 0.117; p = 0.021). Patients in the highest %CV tertile were associated with a higher prevalence of diabetic macroangiopathy than those in the lowest %CV tertile in Hp 1 carriers (OR = 2.461 [95% CI, 1.183-5.121], p = 0.016), but not in those with Hp 2-2 genotype (OR = 0.540 [95% CI, 0.245-1.191], p = 0.127). A significant interactive effect of Hp genotypes and %CV on diabetic macroangiopathy was found (p interaction = 0.008)., Conclusion: Hp genotype modifies the effect of GV on diabetic macroangiopathy among Chinese patients with type 2 diabetes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The intestinal barrier comprises a single layer of epithelial cells tightly joined to form a physical barrier. Disruption or compromise of the intestinal barrier can lead to the inadvertent activation of immune cells, potentially causing an increased risk of chronic inflammation in various tissues. Recent research has suggested that specific dietary components may influence the function of the intestinal barrier, potentially offering a means to prevent or mitigate inflammatory disorders. However, the precise mechanism underlying these effects remains unclear. Bovine colostrum (BC), the first milk from cows after calving, is a natural source of nutrients with immunomodulatory, anti-inflammatory, and gut-barrier fortifying properties. This novel study sought to investigate the transcriptome in BC-treated Zonulin transgenic mice (Ztm), characterized by dysbiotic microbiota, intestinal hyperpermeability, and mild hyperactivity, applying RNA sequencing. Seventy-five tissue samples from the duodenum, colon, and brain of Ztm and wild-type (WT) mice were dissected, processed, and RNA sequenced. The expression profiles were analyzed and integrated to identify differentially expressed genes (DEGs) and differentially expressed transcripts (DETs). These were then further examined using bioinformatics tools. RNA-seq analysis identified 1298 DEGs and 20,952 DETs in the paired (Ztm treatment vs. Ztm control) and reference (WT controls) groups. Of these, 733 DEGs and 10,476 DETs were upregulated, while 565 DEGs and 6097 DETs were downregulated. BC-treated Ztm female mice showed significant upregulation of cingulin ( Cgn ) and claudin 12 ( Cldn12 ) duodenum and protein interactions, as well as molecular pathways and interactions pertaining to tight junctions, while BC-treated Ztm males displayed an upregulation of transcripts like occludin ( Ocln ) and Rho/Rac guanine nucleotide exchange factor 2 ( Arhgf2 ) and cellular structures and interfaces, protein-protein interactions, and organization and response mechanisms. This comprehensive analysis reveals the influence of BC treatment on tight junctions (TJs) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway gene expressions. The present study is the first to analyze intestinal and brain samples from BC-treated Ztm mice applying high-throughput RNA sequencing. This study revealed molecular interaction in intestinal barrier function and identified hub genes and their functional pathways and biological processes in response to BC treatment in Ztm mice. Further research is needed to validate these findings and explore their implications for dietary interventions aimed at improving intestinal barrier integrity and function. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

Background: Haptoglobin (HP), a plasma glycoprotein, binds to free hemoglobin and prevents the loss of iron and kidney damage. The variations of HP gene affect its enzyme activity, resulting in varied antioxidant, angiogenic and anti-inflammatory properties. HP 2-2 genotype showed 3.84 fold increased risk for the development of CKD in Taiwan population. With this background, the present work focused to conduct a prospective case-control study in South Indian population to evaluate whether the HP variants are associated to nondialysis (ND) (CKD stages 1-4) and ESRD (CKD stage 5) conditions., Methods and Results: Totally 392 CKD patients (nondialysis, ND; n = 170, end-stage renal disease, ESRD; n = 222) and 202 healthy individuals were enrolled. The blood samples collected from the patients were used to determine biochemical parameters and HP genotyping. Gene frequency and biochemical parameters were statistically analyzed for disease association. Results showed that HP 2-2 genotypes were significantly associated with ND and ESRD disease development compared to controls. Higher HP2-2 genotype frequency showed an increased hazard ratio for overall disease progression among ND patients (hazard ratio = 3.86; 95% CI 1.88 to 7.93; P = 0.0002). Survival analysis also showed that non-HP2-2 patients have a statistically significantly decreased risk for mortality compared to patients with the HP2-2 genotype (ESRD patients hazard ratio = 4.05; P = 0.04)., Conclusion: The present study confirms that HP2-2 polymorphism is statistically associated with the risk of CKD incidence, progression, and mortality among South Indians. Concluding our results, the HP2-2 genotype could be an independent predictor of all-cause mortality and disease progression in patients with CKD., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Aim: Cerebral small-vessel disease (SVD) is prevalent in type 1 diabetes and has been associated with the haptoglobin variant allele Hp1. Contrarily, the Hp2-allele has been linked to cardiovascular disease and the role of haptoglobin-genotype in asymptomatic SVD is unknown. We, therefore, aimed to evaluate the alleles' association with SVD., Methods: This cross-sectional study included 179 neurologically asymptomatic adults with type 1 diabetes (women 53%, mean age 39 ± 7 years, diabetes duration 23 ± 10 years, HbA 1c 8.1 ± 3.2% [65 ± 12 mmol/mol]). Examinations included genotyping (genotypes Hp1-1, Hp2-1, Hp2-2) by polymerase chain reaction, clinical investigation, and magnetic resonance brain images assessed for SVD manifestations (white matter hyperintensities, cerebral microbleeds, and lacunar infarcts)., Results: SVD prevalence was 34.6%. Haptoglobin genotype frequencies were 15.6% (Hp1-1), 43.6% (Hp1-2), and 40.8% (Hp2-2). Only diastolic blood pressure differed between the genotypes Hp1-1, Hp1-2, and Hp2-2 (81 [74-83], 75 [70-80], and 75 [72-81] mmHg, p = 0.019). Haptoglobin genotype frequencies by presence versus absence of SVD were 16.1%; 46.8%; 37.1% versus 15.4%; 41.9%; 42.7% (p = 0.758). Minor allele frequencies were 39.5% versus 36.3% (p = 0.553). Hp1 homozygotes and Hp2 carriers displayed equal proportions of SVD (35.7% vs 34.4%, p > 0.999) and SVD manifestations (white matter hyperintensities 14.3% vs 17.9%, p = 0.790; microbleeds 25.0% vs 21.9%, p = 0.904; lacunar infarcts 0% vs 3.6%, p > 0.999). Hp1-1 was not associated with SVD (OR 1.19, 95% CI 0.46-2.94, p = 0.712) when adjusting for age, blood pressure, and diabetic retinopathy., Conclusions: Although the SVD prevalence was high, we detected no significant association between SVD and haptoglobin-genotype., (© 2023. The Author(s).)

Purpose: To assess whether polymorphisms of haptoglobin (Hp) modify the relationship between dietary iron and the risk of gestational iron-deficiency anemia (IDA)., Methods: This study analyzed 1430 singleton pregnant women aged 20 ~ ≤ 48 years from the 2017-2019 National Nutrition and Health Survey of Pregnant Women in Taiwan. Sociodemographic, blood biochemical, Hp phenotype, and 24-h dietary recall data were collected. Erythropoiesis-related total prenatal supplementation was defined as the reported use of multivitamins and minerals, vitamin B complex, folate, and iron., Results: Distributions of the Hp 1-1, Hp 2-1, and Hp 2-2 phenotypes were 13.6, 39.8, and 46.5%, respectively. Women with the Hp 1-1 phenotype had the lowest mean levels of serum ferritin (p-trend = 0.017), the highest prevalence of gestational ID (p-trend = 0.033) as well as the highest prevalence of gestational IDA (did not reach statistical differences, p-trend = 0.086). A gene-diet interaction on serum ferritin was observed between the Hp 1 and Hp 2 (2-1/2-2) alleles (p < 0.001). An adjusted multivariate logistic regression showed that compared to those with a normal blood iron status and who reported using erythropoiesis-related total prenatal supplements, those who did not had a 4.05-fold [odds ratio (OR) = 4.05 (95% confidence interval (CI) 2.63-6.24), p < 0.001] increased risk of gestational IDA. The corresponding ORs for carriers of the Hp 1 and Hp 2 alleles were 4.78 (95% CI 1.43-15.99) and 3.79 (95% CI 2.37-6.06), respectively., Conclusion: Pregnant women who are Hp 1 carriers are at increased risk for developing IDA if they do not meet the recommended dietary allowance for iron or use erythropoiesis-related prenatal supplements., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The distribution of Haptoglobin (HP) subtypes differs according to race and geography. It was also confirmed that the serum HP concentration was substantially affected by the HP subtypes. This study aimed to investigate the HP subtypes in northern Chinese and to establish reference intervals for the major HP subtypes using the BN II system. 1195 individuals were included in the study, grouped by haptoglobin subtype, and tested for concentrations by BN II System. Analysis of reference range was performed according to the EP28-A3c guideline. The need to establish reference ranges for subtype, gender, and age groupings was confirmed by the Z-test. The 2.5th and 97.5th percentiles were used as the upper and lower limits of the reference interval, respectively. In the population we investigated, the HP2-2 subtype had the highest proportion, accounting for 49.3%, followed by HP2-1 (38.0%), HP1-1 (7.2%). In addition, about 5.5% of individuals had HP del -related subtypes. The concentrations of the major subtypes (HP1-1, HP2-1, HP2-2) were significantly different, and it was necessary to establish reference ranges by grouping according to the results of the Z-test. The reference intervals were as follows: HP1-1, 0.37-2.19 g/L; HP2-1, 0.38-2.12 g/L; HP2-2, 0.12-1.51 g/L. Significant differences in HP concentrations between genders and ages were found, however, it was not necessary to establish separate reference interval since the results of the Z-test was negative. We have established reference ranges of serum haptoglobin concentrations based on subtypes, which are necessary for the clinical application of haptoglobin., (© 2023. The Author(s).)

Background: A connection between plasma levels of haptoglobin (Hp) and Alzheimer's disease (AD) has been shown in several observational studies. It is debatable, nonetheless, how the two are related causally., Objective: To establish the causal relationship between Hp and AD using a two-sample Mendelian randomization (MR) study., Methods: From the extensive genome-wide association studies and FinnGen dataset, summaries and statistics pertaining to AD were gathered. We investigated the possibility of a causal link between Hp and AD using a two-sample MR study. Inverse variance weighting was used as the primary analytical technique, and it was supported by the joint application of complementary analyses and fixed effects meta-analysis to combine results from various sources., Results: Genetically determined Hp was causally associated with AD [odds ratio (OR), 1.05; 95% confidence interval (CI), 1.02 to 1.09; p = 8.96×10-4]; Inverse variance-weighted estimates coming from different data sources were combined in a meta-analysis with consistent findings (OR, 1.03; 95% CI, 1.01 to 1.05; p = 2.00×10-3). The outcomes of the inverse MR analysis showed that AD had no appreciable causal impact on Hp., Conclusion: The present MR analysis shows that higher plasma Hp leads to an increased risk of AD. Strategies for plasma Hp testing may open up new doors for the early diagnosis and prevention of AD.

Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Haptoglobin (Hp), a liver derived acute phase inflammatory protein (APP), has scarcely been studied in juvenile idiopathic arthritis (JIA). Hp can occur in blood as two isoforms (Hp1 and Hp2) in precursor and mature forms. Routine clinical chemistry immunoturbidimetry does not discern these forms. It is unknown how different forms relate to disease activity in JIA. Our aims were to determine allele frequency and plasma concentrations of different Hp forms at higher versus lower JIA disease activity and compare to other APPs., Methods: Plasma from JIA (n = 77) and healthy (n = 42) children were analyzed for apparent Hp allelic frequency and densitometric concentrations of alpha forms by Western blot (WB). Polymerase chain reaction (PCR) (buffy coat) was performed in a subset to estimate conformity with genetics. At higher versus lower juvenile arthritis disease activity score (JADAS27) (which includes erythrocyte sedimentation rate (ESR)), total mature Hp concentration from WB was compared and correlated against immunoturbidimetry and total protein, albumin, serum amyloid A (SAA) and C-reactive protein (CRP)., Results: At 300-fold dilution needed to study mature forms in Western blot, precursors were undetectable. Hp2 contributed most signal in most samples. Hp allele frequency was similar in JIA and controls. Both mature forms, taken separately or by sum, declined following treatment, but remained above concentrations of healthy controls, even in a remission subset that achieved JADAS27 < 1. Densitometry correlated with immunoturbidimetry. Hp concentrations correlated with JADAS27, albumin (negatively), CRP and SAA with immunoturbidimetric method correlating strongest to JADAS27 (Spearman R ~ 0.6, p < 0.0001)., Conclusion: Hp allele frequency in JIA is similar to the general population, indicating that children with JIA should have the same possibility as in healthy children to produce preHp2 (zonulin), thought to increase intestinal permeability. Circulating Hp concentrations largely parallel other APPs and ESR; none of these measures correlate very strongly to JADAS27 score but Hp can be measured from capillary sampling which is impossible with ESR., (© 2022. The Author(s).)

Background: Dimethylarginine dimethylaminohydrolase (DDAH) 1 maintains the bioavailability of nitric oxide by degrading asymmetric dimethylarginine (ADMA). Here, we aimed to investigate the effect of haptoglobin (Hp) genotype on the association of ADMA and DDAH 1 polymorphism with diabetic macroangiopathy., Methods: In stage 1, 90 Chinese participants with type 2 diabetes were enrolled to measure a panel of targeted metabolites, including ADMA, using tandem mass spectrometry (BIOCRATES AbsoluteIDQ™ p180 kit). In stage 2, an independent cohort of 2965 Chinese patients with type 2 diabetes was recruited to analyze the effect of Hp genotype on the association between DDAH 1 rs233109 and diabetic macroangiopathy. Hp genotypes were detected using a validated assay based on the TaqMan method. DDAH 1 rs233109 was genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using the MassARRAY platform., Results: In stage 1, serum ADMA levels correlated with common Hp genotypes (β ± SE = - 0.049 ± 0.023, P = 0.035), but not with diabetic macroangiopathy (P = 0.316). In stage 2, the distribution of DDAH 1 rs233109 genotype frequencies was 15% (CC), 47% (TC), and 38% (TT), which was in Hardy-Weinberg equilibrium (P = 0.948). A significant Hp genotype by rs 233109 genotype interaction effect on diabetic macroangiopathy was found (P = 0.017). After adjusting for confounders, patients homozygous for rs233109 CC were more likely to develop diabetic macroangiopathy than those carrying TT homozygotes in the Hp 2-2 subgroup [odds ratio = 1.750 (95% confidence interval, 1.101-2.783), P = 0.018]., Conclusion: Hp genotype affects the association between DDAH 1 rs233109 and diabetic macroangiopathy in Chinese patients with type 2 diabetes., (© 2022. The Author(s).)

The exon copy number variant in the haptoglobin gene is associated with cardiovascular and kidney disease. For stroke, previous research is inconclusive. We aimed to study the relationship between the haptoglobin Hp1/2 genotype and stroke in individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We included two partially overlapping cohorts: one with haptoglobin genotypes determined using genotyping for 179 individuals with stroke and 517 matched control subjects, and the other using haptoglobin genotype imputation for a larger cohort of 500 individuals with stroke and 3,806 individuals without stroke. We observed no difference in the Hp1-1, Hp2-1, and Hp2-2 genotype frequencies between individuals with or without stroke, neither in the genotyping nor the imputation cohorts. Haptoglobin genotypes were also not associated with the ischemic or hemorrhagic stroke subtypes. In our imputed haptoglobin cohort, 61% of individuals with stroke died during follow-up. However, the risk of death was not related to the haptoglobin genotype. Diabetic kidney disease and cardiovascular events were common in the cohort, but the haptoglobin genotypes were not associated with stroke when stratified by these complications. To conclude, the Hp1/2 genotypes did not affect the risk of stroke or survival after stroke in our cohort with type 1 diabetes., (© 2022 by the American Diabetes Association.)

Haptoglobin (Hp) is a hemoglobin-binding serum glycoprotein. Some variations in the Hp gene (HP) or Hp-related gene (HPR), including a single-nucleotide polymorphism in intron 2 of HRP, rs2000999, and a complete deletion of the HP gene (HP de l ), one of the rare variants of HP, have been reported to correlate with the serum cholesterol concentration as well as the serum Hp concentration. In this study, we developed a duplex dual-labeled fluorescence probe-based method to simultaneously determine the rs2000999 G > A polymorphism by melting curve genotyping and the zygosity of HP de l by endpoint genotyping. This method was then validated by using the genomic DNA from 94 Japanese subjects for whom genotypes of rs2000999 and HP del zygosity had already been determined. The results obtained with this method were in perfect agreement with the previous ones. Thus, the present method enables us to estimate these two polymorphisms in relatively large-scale groups of subjects, especially in Asian populations where the HP del is distributed., (© 2022 Wiley-VCH GmbH.)

Haptoglobin (Hp) is an abundant plasma protein scavenging hemoglobin (Hb) via CD163 on macrophages. This process consumes Hp, which therefore negatively correlates to hemolysis. However, exact measurements of Hp plasma levels are complicated by different phenotypes (Hp1-1, Hp2-1, and Hp2-2) forming different oligomeric states with differences in immunoreactivity. In addition, humans have an immune-cross-reactive Hp-related protein. In the present study, we developed Hp-specific monoclonal antibodies for an accurate Hp analysis of the different Hp phenotypes in a panel of 112 anonymous samples from hospitalized individuals subjected to routine Hp immunoturbidimetric measurements. The data revealed immunoturbidimetry as a reliable method in most cases but also that the use of non-phenotype-specific calibrators leads to substantial bias in the measurement of the Hp-concentration, non at least in Hp1-1 individuals. Furthermore, analysis of the Hb-dependence of the CD163 interaction with Hp1-1 and Hp2-2 showed that a higher 'cost-effectiveness' in the consumption of dimeric Hp1-1 versus multimeric Hp phenotypes is a likely contribution to the observed differences in the plasma levels of the Hp phenotypes. In conclusion, the determination of Hp phenotype and the use of phenotype-specific calibrators are essential to obtain a precise estimate of the Hp level in healthy and diseased individuals.

Haptoglobin-related protein (Hpr) is a plasma protein with high sequence similarity to haptoglobin (Hp). Like Hp, Hpr also binds hemoglobin (Hb) with high affinity, but it does not bind to the Hb-Hp receptor CD163 on macrophages. The Hpr concentration is markedly lower than Hp in plasma and its regulation is not understood. In the present study, we have developed non-crossreactive antibodies to Hpr to analyze the Hpr concentration in 112 plasma samples from anonymized individuals and compared it to Hp. The results show that plasma Hpr correlated with Hp concentrations (rho = 0.46, p  = .0001). Hpr accounts for on average 0.35% of the Hp/Hpr pool but up to 29% at low Hp levels. Furthermore, the Hpr concentrations were significantly lower in individuals with the Hp2-2 phenotype compared to those with the Hp2-1 or Hp1-1 phenotypes. Experimental binding analysis did not provide evidence that Hpr associates with Hp and in this way is removed via CD163. In conclusion, the Hpr concentration correlates to Hp concentrations and Hp-phenotypes by yet unknown mechanisms independent of CD163-mediated removal of Hb-Hp complexes.

Aims: Haptoglobin (Hp) is a multifaceted marker of inflammation, and mediates the interplay between obesity, inflammation, and cardiometabolic dysfunction. However, the role of the Hp phenotype in modulating intermittent fasting (IF)-induced cardiometabolic changes remains to be elucidated., Methods: Hp phenotype was determined for the study subjects. Cardiometabolic markers were assessed before and at the end of four consecutive weeks, dawn to sunset IF., Results: A total of 114 subjects (75 males and 39 females, 38.7 ± 11.7 years, body mass index (BMI) of 30.41 ± 5.09 kg/m 2 ) were recruited. Hp2-2 (n = 55, 48.2 %) and Hp2-1 (n = 53, 46.5 %) were the predominant phenotypes. Significant reductions were observed in serum Hp, IL-6, TNF-α, triglycerides (TG), total cholesterol (TC), LDL, BMI, and fat mass (FM), while a significant elevation was observed in serum CD163, HDL, and IL-10 at the end of the IF month for the whole population. Based on the Hp polymorphism, significant decreases in Hp, BMI, FM, TG, LDL, and TNF-α, with significant increases in HDL and CD163 levels were observed among subjects with Hp2-2 and Hp2-1 phenotypes. A more pronounced reduction in FM was reported in subjects with Hp2-2 in comparison with Hp2-1., Conclusion: Hp gene polymorphism modulates IF-induced changes in cardiometabolic markers., Clinical Trial Registration Number: ISRCTN18205186; https://trialsearch.who.int/?TrialID=ISRCTN18205186., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) is an arrhythmia that involves structural and electrophysiological abnormalities. Many of the AF-related clinical conditions are associated with an increase in inflammatory and oxidative factors. Haptoglobin (Hp) is an acute phase protein whose biological role is to promote clearance of free hemoglobin (Hb). In addition, for being considered an inflammatory marker, Hp represents a protective mechanism against the oxidative effects of Hb. The Hp1-Hp2 polymorphism at Hp locus can lead to three phenotypes related to structural and functional differences in the protein. The objective of this study were to evaluate Hp levels and Hp1-Hp2 polymorphism at Hp locus in patients with AF compared to a control group., Methods and Results: This study included 65 patients with AF and 54 individuals without the arrhythmia. Biochemical parameters were determined using Vitros system, plasma levels of Hp were measured in serum samples by using ELISA method and polymorphisms were verified by PCR technique. Plasma Hp levels, as well as allelic and genotypic frequency, were not associated with AF. The levels of Hp also did not differ among the genotypes according to the applied models., Conclusions: The results suggest that Hp levels and Hp1-Hp2 polymorphism are not associated to AF., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The gut-brain axis hypothesis suggests that interactions in the intestinal milieu are critically involved in regulating brain function. Several studies point to a gut-microbiota-brain connection linking an impaired intestinal barrier and altered gut microbiota composition to neurological disorders involving neuroinflammation. Increased gut permeability allows luminal antigens to cross the gut epithelium, and via the blood stream and an impaired blood-brain barrier (BBB) enters the brain impacting its function. Pre-haptoglobin 2 (pHP2), the precursor protein to mature HP2, is the first characterized member of the zonulin family of structurally related proteins. pHP 2 has been identified in humans as the thus far only endogenous regulator of epithelial and endothelial tight junctions (TJs). We have leveraged the Zonulin-transgenic mouse (Ztm) that expresses a murine pHP2 (zonulin) to determine the role of increased gut permeability and its synergy with a dysbiotic intestinal microbiota on brain function and behavior. Here we show that Ztm mice display sex-dependent behavioral abnormalities accompanied by altered gene expression of BBB TJs and increased expression of brain inflammatory genes. Antibiotic depletion of the gut microbiota in Ztm mice downregulated brain inflammatory markers ameliorating some anxiety-like behavior. Overall, we show that zonulin-dependent alterations in gut permeability and dysbiosis of the gut microbiota are associated with an altered BBB integrity, neuroinflammation, and behavioral changes that are partially ameliorated by microbiota depletion. Our results suggest the Ztm model as a tool for the study of the cross-talk between the microbiome/gut and the brain in the context of neurobehavioral/neuroinflammatory disorders.

Background: Breast cancer is the leading cause of mortality among women, with over a million cases recorded globally. Haptoglobin (Hp) protein and genotypes play important roles in cancer predisposition and progression, but studies have reported varying outcomes in populations., Aim: The association of Hp genotypes in breast cancer patients with malaria has not been investigated in Nigerians, which is the aim of our study. In healthy women (control; n = 279) and clinically diagnosed breast cancer patients (breast cancer; n = 70)., Methods: Haptoglobin genotypes and Plasmodium falciparum cyclooxygenase III genes were detected by polymerase chain reaction (PCR). Proportions were compared, and the test of association was carried out with a significance level set at P < 0.05., Results: Overall, 311 of 349 (89%) individuals had malaria infection with similar proportions in breast cancer (63 of 70) and healthy control group (248 of 279); malaria incidence was, however, lower in Hp 2-2 breast cancer patients (P = 0.04). The prevalence of Hp genotypes was Hp 1-1 (78.2%), Hp 2-1 (7.2%), and 2-2 (14.6%). In breast cancer groups, Hp 2-2 genotype was significantly lower with 3 (4.2%) of 70 vs. 48 (17.2%) of 279 in control group (P = 0.006)., Conclusions: The results of the study show low Hp 2-2 genotype relative to other genotypes in breast cancer patients; we conclude that low Hp 2-2 genotype is associated with lower malaria risk in breast cancer Nigerian women. It is important to further understand the roles malaria, Hp, and other genotypes play in the pathogenesis of aggressive breast cancer commonly seen in Nigerian women., Competing Interests: None

Background: 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., Methods: 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., Results: 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., Conclusions: Circulating Hp may be a valuable biomarker for assessing muscle health and physical capacity in CHF., Competing Interests: Declaration of Interest The authors declare that there is no conflict of interest., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Thrombotic microangiopathy, hemolysis and acute kidney injury are typical clinical characteristics of hemolytic-uremic syndrome (HUS), which is predominantly caused by Shiga-toxin-producing Escherichia coli. Free heme aggravates organ damage in life-threatening infections, even with a low degree of systemic hemolysis. Therefore, we hypothesized that the presence of the hemoglobin- and the heme-scavenging proteins, haptoglobin and hemopexin, respectively impacts outcome and kidney pathology in HUS. Here, we investigated the effect of haptoglobin and hemopexin deficiency (haptoglobin -/- , hemopexin -/- ) and haptoglobin treatment in a murine model of HUS-like disease. Seven-day survival was decreased in haptoglobin -/- (25%) compared to wild type mice (71.4%), whereas all hemopexin -/- mice survived. Shiga-toxin-challenged hemopexin -/- mice showed decreased kidney inflammation and attenuated thrombotic microangiopathy, indicated by reduced neutrophil recruitment and platelet deposition. These observations were associated with supranormal haptoglobin plasma levels in hemopexin -/- mice. Low dose haptoglobin administration to Shiga-toxin-challenged wild type mice attenuated kidney platelet deposition and neutrophil recruitment, suggesting that haptoglobin at least partially contributes to the beneficial effects. Surrogate parameters of hemolysis were elevated in Shiga-toxin-challenged wild type and haptoglobin -/- mice, while signs for hepatic hemoglobin degradation like heme oxygenase-1, ferritin and CD163 expression were only increased in Shiga-toxin-challenged wild type mice. In line with this observation, haptoglobin -/- mice displayed tubular iron deposition as an indicator for kidney hemoglobin degradation. Thus, haptoglobin and hemopexin deficiency plays divergent roles in Shiga-toxin-mediated HUS, suggesting haptoglobin is involved and hemopexin is redundant for the resolution of HUS pathology., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Haptoglobin related protein (Hpr) is a component of the trypanosome lytic factor (TLF), a complex acting in the innate immune response against African trypanosomes. Like haptoglobin (Hp), Hpr binds hemoglobin (Hb) in the blood, but unlike Hp, Hpr does not bind the CD163 receptor. Moreover, unlike Hp, Hpr retains the N -terminal signal peptide that is required for the association with Apolipoprotein L-1 (ApoL-1), a component of the TLF complex. Here, the molecular model of human Hpr has been built based on the high sequence identity with human Hp (91%). The structural bases of Hpr:Hpr dimerization and Hpr recognition by Hb and Trypanosoma brucei brucei Hp receptor ( Tb HpHbR) have been analyzed in parallel with those of Hp:Hp, Hp:Hb, and Tb HpHbR:Hp:Hb complexes. We show that the Cys33-Cys33 intermolecular disulfide bridge that stabilizes the Hp1:Hp1 complex is replaced by the Phe33, Pro34, and Phe48 hydrophobic core in the Hpr:Hpr dimer. Moreover, we show that the N -terminal peptide of Hpr participates in the stabilization of the Hpr:Hpr dimer. Thus, the N -terminal peptide seems to have been retained in Hpr to mediate its critical role in the human innate immunity towards Trypanosoma brucei brucei infection.Communicated by Ramaswamy H. Sarma.

Background: Major histocompatibility complex (MHC) is the best characterised genetic region associated with adaptive immune responses, including humoral and cell-mediated immunities., Objectives: In this study, the association of MHC class II alleles with inflammatory cytokines and acute-phase proteins was evaluated in sheep population., Methods: Allelic diversity of second exon of ovine DRB1 locus (Ovar-DRB1.2) was determined in 100 indigenous Iranian Lori-Bakhtiari fat-tailed sheep using restriction fragment length polymorphism and direct sequencing methods. The association of DRB1.2 alleles with inflammatory cytokines (interleukin-1β, IL-1β; IL-6 and tumour necrosis factor-α) and acute-phase proteins (serum amyloid A, alpha-1-acid glycoprotein and haptoglobin) was examined using generalised linear model and multivariate regression analysis., Results: Seven distinct RsaI restriction patterns and fourteen alleles were identified in this population. Allele DRB1*2101 showed a negative influence on the IL-6 response and was associated with lower serum level of IL-6. DRB1.2 heterozygous individuals also showed higher haptoglobin concentration than homozygotes., Conclusions: These results provide additional support for the association between Ovar-DRB1 alleles and regulation of immune responses in sheep population. Description of MHC polymorphism and its role in the controlling of immune responses will increase our understanding of host-pathogen interactions, and ultimately facilitate the selection of disease-resistant flocks in genetic breeding programs., (© 2021 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in the regulation of iron bioavailability. The aim of this study was to examine dysregulation of the CD163-haptglobin axis in COPD. We measured soluble CD163 (sCD163) and haptoglobin levels in sputum supernatants by enzyme-linked immunosorbent assay (ELISA) and sputum macrophage CD163 and haptoglobin expression by flow cytometry in COPD patients and controls. SCD163 levels were lower in COPD patients compared to controls ( p = 0.02), with a significant correlation to forced expiratory volume in 1 s (FEV1)% predicted (rho = 0.5, p = 0.0007). Sputum macrophage CD163 expression was similar between COPD patients and controls. SCD163 levels and macrophage CD163 expression were lower in COPD current smokers compared to COPD ex-smokers. Haptoglobin levels were not altered in COPD patients but were regulated by genotype. Macrophage CD163 and haptolgobin expression were significantly correlated, supporting the role of CD163 in the cellular uptake of haptoglobin. Our data implicates a dysfunctional CD163-haptoglobin axis in COPD, which may contribute to disease pathophysiology, presumably due to reduced clearance of extracellular iron.

We examined the relationship between zonulin and gastric motility in critical care patients and a translational mouse model of systemic inflammation. Gastric motility and haptoglobin (HP) 2 isoform quantification, proxy for zonulin, were examined in patients. Inflammation was triggered by lipopolysaccharide (LPS) injection in C57Bl/6 zonulin transgenic mouse (Ztm) and wildtype (WT) mice as controls, and gastro-duodenal transit was examined by fluorescein-isothiocyanate, 6 and 12 h after LPS-injection. Serum cytokines and zonulin protein levels, and zonulin gastric-duodenal mRNA expression were examined. Eight of 20 patients [14 years, IQR (12.25, 18)] developed gastric dysmotility and were HP2 isoform-producing. HP2 correlated with gastric dysmotility (r = - 0.51, CI - 0.81 to 0.003, p = 0.048). LPS injection induced a time-dependent increase in IL-6 and KC-Gro levels in all mice (p < 0.0001). Gastric dysmotility was reduced similarly in Ztm and WT mice in a time-dependent manner. Ztm had 16% faster duodenal motility than WT mice 6H post-LPS, p = 0.01. Zonulin mRNA expression by delta cycle threshold (dCT) was higher in the stomach (9.7, SD 1.4) than the duodenum (13.9, SD 1.4) 6H post-LPS, p = 0.04. Serum zonulin protein levels were higher in LPS-injected mice compared to vehicle-injected animals in a time-dependent manner. Zonulin correlated with gastric dysmotility in patients. A mouse model had time-dependent gastro-duodenal dysmotility after LPS-injection that paralleled zonulin mRNA expression and protein levels., (© 2021. The Author(s).)

Sickle cell anemia is hallmarked by hemolysis, which releases hemoglobin (Hb) into the plasma promoting vaso-occlusive crisis (VOC). Haptoglobin (Hp) clears free Hb and decreases Hb-related pathophysiology in sickle cell anemia. There are two alleles (HP1 and HP2) and three genotypes (HP1-1, HP1-2 and HP2-2) of Hp with different frequencies in different populations. This study involved Hp level and genotype among normal and sickle cell anemia patients with varying severity of VOC. A total of 297 sickle cell anemia patients and 98 healthy controls were selected for the study. The sickle cell anemia patients were categorized as 'mild-phenotype' with no pain episodes and 'severe-phenotype' as having three or more acute pain episodes in the preceding 12 months. The Hp level was significantly lower ( p  < 0.001) in sickle cell patients anemia than controls; HP1-1 genotype had a higher Hp level compared to HP1-2 and HP2-2 ( p  < 0.05). Turkey-Kramer multiple comparison tests showed that mild and severe phenotypes have significant differences ( p  < 0.05) in Hb F%, Hb, platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct-bilirubin (Bil-D), total-bilirubin (Bil-T), lactate dehydrogenase (LDH) and Hp level. Pearson correlation revealed that Hp level has a positive ( p  < 0.05) correlation with Hb F%, Hb, packed cell volume (PCV) and serum urea; in contrast its level is negatively correlated with AST, ALT, Bil-T and LDH. A significantly higher frequency of HP2 allele and HP2-2 genotypes was found in severe phenotypes. In the studied population, it was found that higher HP2 frequency, low Hp level and more hemolysis favors the onset of VOC in sickle cell anemia.

Cryptogenic elevation of transaminases in childhood can in a few instances be linked to rare hereditary causes. In this paper, a 7-year old girl is reported who was diagnosed with elevated transaminases of unknown origin since infancy. A liver biopsy showed bridging fibrosis, pale eosinophilic intracytoplasmic hepatocellular inclusions and enlarged endoplasmic reticulum cisternae in the hepatocytes. Whole-exome sequencing revealed a homozygous in-frame deletion of 3 base pairs in the haptoglobin gene. The patient is anhaptoglobinemic measured by standard laboratory turbidometry, which was confirmed by Western Blotting and thereby shown to affect both protein chains of haptoglobin. A polyclonal antibody revealed haptoglobin retention in hepatocytes suggesting a defect in haptoglobin secretion. A novel, previously unknown haptoglobin storage disease is suspected to be the reason for the elevated liver enzymes and tissue abnormalities in this patient. The pathophysiology appears to be similar to endoplasmic reticulum storage diseases like alpha-1-antitrypsin-deficiency., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Cell-free hemoglobin (Hb) is a driver of disease progression in conditions with intravascular or localized hemolysis. Genetic and acquired anemias or emergency medical conditions such as aneurysmal subarachnoid hemorrhage involve tissue Hb exposure. Haptoglobin (Hp) captures Hb in an irreversible protein complex and prevents its pathophysiological contributions to vascular nitric oxide depletion and tissue oxidation. Preclinical proof-of-concept studies suggest that human plasma-derived Hp is a promising therapeutic candidate for several Hb-driven diseases. Optimizing the efficacy and safety of Hb-targeting biotherapeutics may require structural and functional modifications for specific indications. Improved Hp variants could be designed to achieve the desired tissue distribution, metabolism, and elimination to target hemolytic disease states effectively. However, it is critical to ensure that these modifications maintain the function of Hp. Using transient mammalian gene expression of Hp combined with co-transfection of the pro-haptoglobin processing protease C1r-LP, we established a platform for generating recombinant Hp-variants. We designed an Hpβ-scaffold, which was expressed in this system at high levels as a monomeric unit (mini-Hp) while maintaining the key protective functions of Hp. We then used this Hpβ-scaffold as the basis to develop an initial proof-of-concept Hp fusion protein using human serum albumin as the fusion partner. Next, a hemopexin-Hp fusion protein with bispecific heme and Hb detoxification capacity was generated. Further, we developed a Hb scavenger devoid of CD163 scavenger receptor binding. The functions of these proteins were then characterized for Hb and heme-binding, binding of the Hp-Hb complexes with the clearance receptor CD163, antioxidant properties, and vascular nitric oxide sparing capacity. Our platform is designed to support the generation of innovative Hb scavenger biotherapeutics with novel modes of action and potentially improved formulation characteristics, function, and pharmacokinetics.