Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases

Haptoglobin (Hp) is a plasma alpha(2)-glycoprotein which binds free haemoglobin, thus preventing oxidative damage. The complex is rapidly removed from the circulation by a specific receptor (CD163) found on macrophages. Three major subtypes, Hp1-1, Hp2-1 and Hp2-2 are the product of two closely related genes HP(1) and HP(2). The frequency of the HP(1) and HP(2) genes varies worldwide depending on racial origin: the HP(1)frequency varying from about 0.07 in parts of India to over 0.7 in parts of West Africa and South America. Both HP(1) and HP(2) have been linked to susceptibility to various diseases. Such associations may be explained by functional differences between the subtypes in the binding of Hb and its rate of clearance from the plasma. However, there are also corresponding negative reports for disease associations. The conflicting evidence on disease association and the lack of association between disease and particular populations, despite the wide range of HP(1) and HP(2) gene frequencies across the world, may indicate that any associations are marginal.     

Shenfu Injection(参附注射液) Suppresses Inflammation by Targeting Haptoglobin and Pentraxin 3 in Rats with Chronic Ischemic Heart Failure

Objective:To investigate the regulatory effects of Shenfu Injection(SFI,参附注射液) on hemodynamic parameters and serum proteins in rats with post-infarction chronic heart failure(CHF).Methods:Forty-five healthy Wistar rats were randomized into three groups:sham,heart failure(model) and SFI group.The CHF was induced by left coronary artery ligation.Seven days after the surgical operation,animals in the sham group and the model group received saline(6.2 mL/kg/d),while animals in the SFI group received SFI(6.2 mL/kg·d) intraperitoneally.Four weeks later,cardiac hemodynamic parameters were measured via the carotid route.The expression of serum proteins was analyzed by two-dimensional electrophoresis and matrixassisted laser desorption/ionization time-of-flight mass spectrometer(MALDI-TOF MS).Results:Recording of hemodynamic parameters showed that left ventricular systolic pressure(LVSP),maximum rate of left ventricular pressure(+dp/dt_(max)) rise,and maximum rate of left ventricular pressure(-dp/dt_(max)) decrease,while the left ventricular end diastolic pressure(LVEDP) rose in the model group compared to those in the sham group(P0.05).The results of the MALDI-TOF MS indicated that haptoglobin(HP),pentraxin 3(PTX3) and alpha-1-antitrypsin were up-regulated,while serum albumin and 40 S ribosomal protein were down-regulated in the model group(P0.05).Compared with the model group,LVSP,+dp/dt_(max)and-dp/dt_(max) were higher,while LVEDP was lower in the SFI group(P0.05).Expression levels of HP and PTX3 were lower than in the model group(P0.05).Conclusion:SFI could improve hemodynamic function and decrease inflammatory reactions in the pathophysiology of CHF.The serum proteins HP and PTX3 could be potential biomarkers for chronic ischemic heart failure,and they could also be the serum protein targets of SFI.     

Haptoglobin therapy for acute favism: a Japanese boy with glucose-6-phosphate dehydrogenase Guadalajara

Summary. We report the case of a 2-year-old Japanese boy with acute favism who was treated with human haptoglobin products. He had been exhibiting chronic nonspherocytic haemolytic anaemia until the diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency when 14 months old. He suffered a favic crisis at 24 months of age, when the administration of haptoglobin was effective for relieving bilirubinaemia and haemoglobinuria. Serum-free Hb rapidly decreased to normal levels despite the sustained level of serum lactate dehydrogenase. His G6PD gene was G6, Guadalajara. This is the first application of haptoglobin therapy for acute favism and the first reported case of Japanese G6PD deficiency with typical favic crisis. Haptoglobin treatment might be helpful for managing the haemolytic crisis in the disease.     

Haptoglobin phenotypes and in vitro fertilization treatment outcomes

The haptoglobin (Hp) protein has been implicated in various aspects of reproduction. One possible mechanism is through its effect on angiogenesis. Angiogenesis plays a major role in follicle production. The Hp insertion polymorphism results in the production of Hp proteins denoted Hp 1-1, 2-1, and 2-2, with markedly different angiogenic activities. We sought to determine if the number of oocytes aspirated during in vitro fertilization is related to the Hp type and to compare clinical data and treatment outcomes. We conducted a prospective non-interventional study in an academic in vitro fertilization center serving northern Israel. All patients undergoing in vitro fertilization who agreed to have their haptoglobin phenotype and clinical data evaluated anonymously were included. The main outcome measure was the number of oocytes harvested from each aspiration. The groups did not differ regarding ethnicity or BMI, though women with the Hp1-1 phenotype had a longer duration of infertility (p?=?0.037) and a higher gonadotropin requirement (p?=?0.024) to achieve the same treatment outcome. Women with mechanical factor infertility were more likely (p?=?0.042) to have the Hp 1-1/2-1 phenotypes than the Hp2-2 phenotype. There were no differences in the number of oocytes aspirated or the pregnancy rate. In summary, we could not establish a correlation between Hp phenotype and oocyte number or IVF outcomes though the Hp2-2 phenotype may be protective against mechanical factor infertility. Further studies with a larger sample size, particularly concerning the Hp1-1 phenotype, are required in order to extend these results.     

Serum haptoglobin as a novel molecular biomarker predicting colorectal cancer hepatic metastasis

Early detection of liver metastasis is important for improving colorectal cancer (CRC) patient survival. Our previous studies showed haptoglobin was highly expressed in primary CRC tissues, especially in heterochronous metastatic cases. Here, we assessed the potential of serum haptoglobin (sHP) as a biomarker for early detection of CRC liver metastasis by evaluating the sHP in 475 CRC patients and 152 healthy volunteers. In the training set (250 cases), sHP level in CRC‐M1 (1773.18 ± 690.25 ng/mL) were significantly increased as compared to in CRC‐M0 (1544.37 ± 1497.65 ng/mL) or healthy (917.76 ± 571.59 ng/mL). And the high sHP level was correlated with poor survival. Logistic regression analysis revealed that sHP, serum carcinoembryonic antigen (sCEA) and serum carbohydrate antigen 19.9 (sCA19.9) level were the significant parameters for detecting liver metastasis. In leave‐one‐out‐cross‐validation, these three markers resulted in 89.1% sensitivity and 85.8% specificity for hepatic metastasis detection. In an independent test set (225 cases), receiver operating characteristic curve analysis of sHP in CRC liver metastasis showed an area under the curve of 0.735, with a sensitivity of 87.2% and a specificity of 59.9%. Combination of sHP, sCEA and sCA19.9 improved diagnostic accuracy to 0.880, with a sensitivity of 88.5% and a specificity of 87.8%. Silencing of HP by specific shRNA significantly inhibited the LOVO and SW620 cell invasion, and suppressed xenograft tumor invasive growth. In summary, these results demonstrate that sHP is associated with poor prognosis of CRC patients and that HP promotes colorectal cancer cell invasion. sHP combining with sCA19.9 and sCEA may be used as accurate predictors of CRC liver metastasis.     

硫氧还蛋白1、触珠蛋白在非小细胞肺癌患者血清中的表达及临床意义

目的:探讨硫氧还蛋白1（Trx1）、触珠蛋白（Hp）在非小细胞肺癌（NSCLC）患者血清中的表达及临床意义。方法:选取2016年1月至2018年12月我院呼吸科收治的非小细胞肺癌患者186例（实验组）,另选取我院健康体检人员80例（对照组）,检测两组血清Trx1、Hp水平,分析不同临床病理特征血清Trx1、Hp差异,分析血清Trx1、Hp对预测非小细胞肺癌发生的诊断效能。结果:实验组患者血清Trx1、Hp水平分别高于对照组血清Trx1、Hp水平,差异有统计学意义（P＜0.05）。NSCLC患者肿瘤直径≥3 cm、肿瘤低分化、TNM分期（Ⅲ+Ⅳ期）、存在淋巴结转移分别与患者肿瘤直径＜3 cm、肿瘤中+高分化、TNM分期（Ⅰ+Ⅱ期）、无淋巴结转移血清Trx1、Hp水平相比,差异有统计学意义（P＜0.05）。ROC曲线结果示:Trx1、Hp联合检测NSCLC曲线下面积为0.840,敏感度和特异度分别为0.882和0.827。Kaplan-Meier分析示:血清Trx1、Hp低水平NSCLC患者的生存率高于高水平患者（P＜0.05）。结论:血清Trx1、Hp在NSCLC中表达水平升高,血清Trx1、Hp水平变化与NSCLC病情进展有关,血清Trx1、Hp联合检测对预测NSCLC发生、预后有重要意义。     

N‐glycosylation status of β‐haptoglobin in sera of patients with colon cancer,chronic inflammatory diseases and normal subjects

N‐glycosylation status of purified β‐haptoglobin from sera of 17 patients, and from sera of 14 healthy volunteer subjects, was compared by blotting with various lectins and antibodies. Patients in this study were diagnosed as having colon cancer through histological examination of each tumor tissue by biopsy. Blotting index of serum β‐haptoglobin with Aleuria aurantia lectin (AAL) was clearly higher for cancer patients than for healthy subjects. No such distinction was observed for blotting with three other lectins and two monoclonal antibodies. To determine tumor‐associated reactivity of AAL binding as compared to inflammatory processes in colonic tissues, β‐haptoglobin separated from sera of 5 patients with Crohn's disease (CD), and 4 patients with ulcerative colitis (UC), was studied. All these cases, except one case of UC, showed AAL index lower than that in cancer cases, similarly to healthy subjects. The higher AAL binding of β‐haptoglobin in colon cancer patients than in healthy subjects appeared to be due to α‐L‐fucosyl residue, since it was eliminated by bovine kidney α‐fucosidase treatment. N‐linked glycans of serum haptoglobin from colon cancer patients vs. healthy subjects were released by N‐glycanase, fluorescence‐labeled, and subjected to normal‐phase high performance liquid chromatography (NP‐HPLC). Glycan structures were determined based on glucose unit (GU) values and their changes upon sequential treatment with various exoglycosidases. Glycosyl sequences and their branching status of glycans from 14 cases of serum β‐haptoglobin were characterized. The identified glycans were sialylated or nonsialylated, bi‐antennary or tri‐antennary structures, with or without terminal fucosylation.