Haptoglobin Polymorphism Research Articles

Haptoglobin polymorphism, vitamin E and mortality: the Ludwigshafen Risk and Cardiovascular Health Study

ObjectiveIn humans, haptoglobin (Hp) exists in two allelic forms, Hp1 and Hp2, that differ significantly in their ability to protect the organism from oxidative stress. It has been proposed that in patients with diabetes mellitus carriers of the Hp2-2 genotype may benefit from vitamin E supplementation. Aim of our study was to investigate if there is evidence regarding a potential interaction between the Hp polymorphism and vitamin E with regard to mortality in individuals at medium-to-high cardiovascular risk with and without diabetes mellitus.Research design and methodsData from 3176 participants of the Ludwigshafen Risk and Cardiovascular Health study, a monocentric hospital-based study of patients referred for coronary angiography, were analysed using Cox proportional hazard regression.ResultsParticipants with the Hp2-2 genotype demonstrated significantly lower Hp levels, while carriers of at least one Hp-2 allele displayed elevated levels of the inflammatory markers high-sensitive C reactive protein and serum amyloid A. No notable differences in comorbidities were observed among the various HP genotype groups. While the HP genotype showed no direct association with mortality, a borderline significant correlation between α-tocopherol plasma concentration and overall mortality was noted. An interaction between vitamin E status and the HP genotype regarding mortality risk was evident, particularly among patients with diabetes mellitus, with a p value of 0.021 for the interaction term. In restricted cubic splice analysis, patients with diabetes mellitus who are carriers of the Hp2-2 genotype seem to benefit from higher γ-tocopherol concentrations whereas for the other genotype groups there was a direct association with mortality risk.ConclusionParticularly in patients with diabetes mellitus we could show a significant interaction of γ-tocopherol plasma concentration and HP genotype. Carriers of the Hp2-2 genotype seemed to benefit from higher plasma concentrations of γ-tocopherol. Further research is warranted to elucidate the underlying mechanisms and potential therapeutic implications in cardiovascular disease management.

Contribution of haptoglobin phenotypic variation to the presence of hyperhomocysteinemia in type 2 diabetics with and without angiopathy.

The genetic polymorphism of haptoglobin (Hp) has been associated with several cardiovascular risk factors, but a possible relationship between Hp phenotypic variation and increased levels of homocysteine (Hcy) and cysteine (Cy) is still unknown. The objective of this study is to evaluate the relationship between the Hp polymorphism and hyperhomocysteinemia (HHcy) and hypercysteinemia (HCy) in type 2 diabetics (T2D) with and without angiopathy (AGP). A case-control study was carried out on 293 adults: Group I (GI) - 75 subjects with T2D and AGP; Group II (GII) - 75 subjects with T2D without AGP; Group III (GIII) - 143 controls. Plasma levels of Hcy, Cy and vitamin B6 were measured by high performance liquid chromatography (HPLC) and vitamins B9 and B12 determined by electrochemiluminescence (ECL). The Hp polymorphism was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and peroxidase staining. The results were analyzed in SPSS®, version 26.0 with a significance of 95%. Mean Hcy concentrations were significantly lower in carriers of the Hp2-2 phenotype (6.14 µM; p = 0.046) compared to the other genotypes. The presence of Hp2-1 is associated with an approximately 3.3 times greater probability of occurrence of HHcy (p = 0.015) and 3.7 times greater probability occurrence of HCy (p = 0.021) in T2D with AGP. The presence of the Hp2-1 phenotype is associated with the predisposition of HHcy and HCy in individuals with T2D and AGP, possibly through a positive heterosis mechanism. Carriers of the Hp2-2 phenotype appear to have a greater activation of the transsulfuration pathway in the Hcy cycle and consequent protection for its accumulation.

Changes in haptoglobin genotype-based gene expressions upon the observance of dawn-to-dusk intermittent fasting: a prospective cohort study on overweight and obese individuals.

Intermittent fasting (IF) has been reported to be involved in ameliorating oxidative stress and lessening the systemic-low grade inflammation that predisposes to chronic diseases. Gene polymorphism is currently a main determining factor for the metabolic responses to different dietary and lifestyle modifications. The current study was designed to explore the effect of observing four-week, dawn to dusk IF by participants with obesity on gene expression of the anti-inflammatory CD163, oxidative stress, and bioenergetics enzymes (SOD2, Nrf2, and TFAM), as well as metabolic and cellular regulatory genes (SIRT1 and SIRT3). Further, the study aimed to find out how haptoglobin (Hp) polymorphism modulates gene expression of the aforementioned genes and to determine changes in relative gene expressions of the aforementioned six genes based on Hp polymorphism in response to IF. Haptoglobin genotype was determined for the study subjects, and gene expressions were determined using qPCR. Gene expressions were assessed before and at the end of four consecutive weeks, dawn to sunset IF. The expressions of CD163, SOD, NfF2, and TFAM genes have significantly increased at the end of IF. At the same time, SIRT3 significantly decreased, implying that observing four consecutive weeks of dawn-to-dusk IF may enhance antioxidative stress response and reduce systemic inflammation. Participants with genotypes Hp2-1 and Hp2-2 revealed upregulation of the antioxidant genes in response to the metabolic stress induced by IF compared with Hp1-1, implying that Hp polymorphism plays a key role in shaping the body's response to dietary modifications such as fasting.

Association between haptoglobin polymorphism and coronary artery disease: a meta-analysis.

Previous studies have investigated the association between the haptoglobin rs72294371 polymorphism and coronary artery disease (CAD) risk, but the results are controversial and uncertain. Therefore, this study aimed to systematically review the literature on haptoglobin polymorphism and susceptibility to CAD. PubMed, Embase, Web of Science, Cochrane Library, and Wanfang databases were used to identify relevant studies from their inception to April 2024. The pooled odds ratio (OR) with corresponding 95% confidence interval (CI) were used to assess the strength of the association. An OR value greater than one suggested an increased risk; otherwise, it suggested a protective risk. A total of 15 studies comprising 8,632 individuals (2,988 cases and 5,644 controls) were included. In the current meta-analysis, a significant association between haptoglobin polymorphism and CAD was found under recessive model (OR:0.74, 95% CI:0.60-0.92), dominant model (OR: 0.82, 95% CI: 0.71-0.95), homozygote model (OR: 0.70, 95% CI: 0.53-0.92), and allelic genetic model (OR: 0.80, 95% CI: 0.69-0.94). In the analysis stratified by ethnicity, a statistically significant association was observed in Asians rather than Caucasian population. This meta-analysis indicates that haptoglobin polymorphism is associated with CAD susceptibility, especially in Asians.

Haptoglobin gene polymorphism and iron profile in sickle cell disease patients with inflammation in Yaounde, Cameroon.

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. 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. 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. 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.

Predictors of treatment failure of non-steroidal anti-inflammatory drugs in patients with axial spondyloarthritis with focus on haptoglobin, haptoglobin polymorphism and zonulin.

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 4weeks (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.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease.

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. 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. 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. 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.

Haptoglobin polymorphism modulates cardiometabolic impacts of four consecutive weeks, dawn to sunset Ramadan intermittent fasting among subjects with overweight/obesity

AimsHaptoglobin (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. MethodsHp phenotype was determined for the study subjects. Cardiometabolic markers were assessed before and at the end of four consecutive weeks, dawn to sunset IF. ResultsA total of 114 subjects (75 males and 39 females, 38.7 ± 11.7 years, body mass index (BMI) of 30.41 ± 5.09 kg/m2) 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. ConclusionHp gene polymorphism modulates IF-induced changes in cardiometabolic markers.Clinical Trial Registration number: ISRCTN18205186; https://trialsearch.who.int/?TrialID=ISRCTN18205186.

Haptoglobin polymorphism affects its N-glycosylation pattern in serum

IntroductionHaptoglobin (Hp) is an abundant acute-phase protein secreted mainly by the liver into the bloodstream. There are three Hp protein phenotypes (Hp type 1–1, 2–1, and 2–2), which differ in the number of α- and β-chains, type of α-chain (the β-chain type remains the same in all the Hp phenotypes), and the polymers that they form via disulfide bonds. Hp has four N-glycosylation sites on the β-chain. Glycosylation of Hp has been reported frequently as a potential glycobiomarker for many diseases; however, whether Hp polymorphism affects its glycosylation has not yet been addressed extensively or in depth. ObjectivesThis study investigated the differences between the glycosylation patterns of Hp phenotypes using serum from 12 healthy individuals (four for each Hp phenotype). MethodAn efficient method for isolating Hp from serum was established and subsequently the Hp phenotype of each sample was characterized by immunoblotting. Then, LC-MS/MS analysis of isolated Hp after treatment with three exoglycosidases (sialidase, α2-3 neuraminidase, Endo F3) was performed to characterize the glycosylation pattern of Hp for each individual sample. ResultsThe data reveal significant differences among the branching, sialylation, and fucosylation of Hp types, documenting the effect of Hp polymorphism on its glycosylation. ConclusionOverall, the study suggests that Hp phenotype characterization should be considered during the investigation of Hp glycosylation.

Plasma Haptoglobin and Group-specific Component Phenotypic Variants Increase the Risk of Chronic Kidney Disease

ABSTRACT The researchers studied the correlation of Haptoglobin (HP) and Group-specific Component (GC) plasma protein biomarkers in chronic kidney disease (CKD) patients and non-CKD controls using discontinuous-polyacrylamide gel electrophoresis. The results showed a significant difference between the CKD and control clusters of 2-2 variants for HP (p=0.0036) and GC (p= 0.0033). The current research indicates 2-2 phenotype is an independent risk determinant for CKD, while risk analysis reports odds value &gt;1 for both protein polymorphisms signifying an effective risk towards CKD. The multifactor dimensional reduction analysis also detailed HP and GC markers have a strengthening and stronger association and are causative for CKD development. Collectively, the findings signify a potential risk of plasma HP and GC polymorphisms being susceptible to CKD and their key role in the deterioration of kidney functions.

Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients.

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.

Relation between haptoglobin polymorphism and oxidative stress status, lipid profile, and cardiovascular risk in sickle cell anemia patients.

ObjectiveThe haptoglobin (Hp) gene located on chromosome 16q22 exhibits a polymorphism that can impact its capacity to inhibit the deleterious oxidative activity of free hemoglobin. We aimed to determine the influence of Hp polymorphism on oxidative stress, lipid profile, and cardiovascular risk in Cameroonian sickle cell anemia patients (SCA patients).MethodThe Hp genotypes of 102 SCA patients (SS), 60 healthy individuals (AA), and 55 subjects with sickle cell trait (AS) were determined by allele‐specific PCR, and the blood parameters were assessed using standard methods.ResultsHp2‐2 genotype was significantly (P < .05) present in SS (54%) than in AS (42%) and AA (38%). Levels of catalase and cell reactive protein were higher, while levels of total antioxidant capacity, triglycerides, low‐density lipoprotein cholestetol, blood pressure, Framingham score, and body mass index were lower in the SCA patients. These parameters appeared to be unrelated to the haptoglobin genotypes. SCA patients with Hp1‐1 genotype presented a higher oxidative stress index (0.53 ± 0.31) than those with Hp2‐1 (0.33 ± 0.18). Lipid profile and cardiovascular risk were not significantly different between various Hp genotypes in SCA patients.ConclusionHaptoglobin polymorphism did not affect lipid profile, cardiovascular risk, and oxidative stress status of SCA patients. Nevertheless, SCA patients with Hp1‐1 genotype tended to be more prone to oxidative stress than those with Hp2‐1.

Haptoglobin 1-1 Isoform Predicts Higher Serum Haptoglobin Concentration and Lower Multiorgan Failure Risk in Sickle Cell Disease

▪Haptoglobin (HP) is the major scavenger of cell-free hemoglobin in circulation. When haptoglobin is depleted, cell-free hemoglobin can lead to organ damage through direct oxidative injury, upregulation of inflammatory pathways, and depletion of nitric oxide. A common polymorphism in HP gives rise to structurally and functionally distinct phenotypes: HP 1-1, HP 2-1, and HP 2-2. In people of African descent, the HP 1-1 and 2-1 phenotypes have been associated with higher serum HP concentrations compared to the HP 2-2 phenotype (PMID 10807979). In hemolytic diseases, such as sickle cell disease (SCD), the consequence of the HP polymorphism is unclear but could influence cell-free hemoglobin processing and susceptibility to organ damage.We first investigated whether the HP isoforms are associated with HP concentrations at steady-state. Between 10/2009 and 6/2018, we recruited 431 SCD patients into a longitudinal registry at our institution during a routine clinic visit, which we defined as steady-state. Baseline clinical and laboratory data were collected at the time of enrolment. The median age of the cohort was 32 (interquartile range [IQR], 24 - 43) years, 43% were male, 76% were SCD SS or Sβ 0-thalassemia genotype, and 46% were on hydroxyurea at the time of enrolment. Genotyping of the HP polymorphisms by PCR demonstrated the HP 1-1 isoform in 30% (n = 129), the HP 2-1 isoform in 47% (n = 203), and the HP 2-2 isoform in 23% (n = 99) of the SCD cohort. Serum samples were available in 244 of the 431 SCD patients at steady-state. Serum concentrations of HP, measured by ELISA, were higher in those with the HP 1-1 isoform compared to the HP 2-1 or 2-2 isoform (Figure). In a linear regression model, independent variables associated with steady-state serum HP concentration included SCD SS or Sβ 0-thalassemia genotype (β -1.8; 95% CI: -2.5 to -1.0; P < 0.001), LDH (natural log β -0.9; 95% CI: -0.2 to -1.6; P = 0.018), hydroxyurea use (β 0.6; 95% CI: 0.1 to 1.1; P = 0.02), and HP 1-1 isoform (β 0.5, 95% CI: 0 to 1.1; P = 0.049), adjusting for age and sex.Between 9/2020 and 5/2021, we collected an additional 38 serum samples from SCD patients during a hospitalization for vaso-occlusive crisis (VOC) and serum samples from 7 SCD patients during a hospitalization for acute chest syndrome. The HP 1-1 isoform was associated with higher serum HP concentrations during VOC and during acute chest syndrome compared to the HP 2-1 or 2-2 isoforms (Figure). Interestingly, the serum HP trended higher from steady-state to VOC and to acute chest syndrome in SCD patients with the HP 1-1 isoform (β +1.1, P = 0.085) but trended lower in those with the HP 2-1 or 2-2 isoform (β -0.5, P = 0.099).Next we tested whether the HP 1-1 isoform is protective against multi-organ failure during hospitalizations for acute chest syndrome. For the longitudinal analysis, we focused on SCD patients with > 6 months of follow up at our institution (n = 391). A multiorgan failure event was defined as organ dysfunction involving at least 2 of the following organ systems: lung, kidney, liver, or central nervous system (PMID 8109600). With a median follow up of 6.8 (IQR, 3.5 - 8.9) years, we observed an acute chest syndrome episode complicated by multiorgan failure in 14% (53/391) of SCD patients. A significantly lower proportion of SCD patients with the HP 1-1 isoform developed a multiorgan failure event versus those with the 2-1 or 2-2 isoforms (5.7% vs. 17.2%, respectively; P < 0.001). On logistic regression analysis, acute chest syndrome with multiorgan failure was associated with the HP 1-1 isoform (OR 0.3, 95% CI: 0.1 to 0.6; P = 0.002) and baseline LDH (natural log OR 2.7, 95% CI: 1.2 - 6.3; P = 0.02), after adjusting for age, sex, SCD genotype and hydroxyurea use.In conclusion, we demonstrate that the HP 1-1 isoform is independently associated with higher serum HP concentrations at steady-state as well as during hospitalizations for VOC or acute chest syndrome compared to the HP 2-1 or 2-2 isoforms. Furthermore, the HP 1-1 isoform is protective against developing the devastating multiorgan failure syndrome during acute chest syndrome episodes. Our findings highlight the clinical significance of the HP isoforms and cell-free hemoglobin scavenging in SCD. Future studies assessing HP induction and scavenging function based on HP isoform may help elucidate high-risk patients for aggressive measures, such as rapid initiation of exchange transfusion therapy or HP replacement therapy. [Display omitted] DisclosuresGordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Evaluation of the relationship between haptoglobin polymorphisms with antioxidant enzymes activity in patients with coronary heart disease

BackgroundAtherosclerosis, the most common pathologic process underlying cardiovascular disease, defines a state of intensified oxidative stress and impaired antioxidative capacity. Haptoglobin (Hp) polymorphisms include three distinct human genotypes (Hp1-1, Hp2-1, and Hp2-2), managing functional differences related to the risk of developing cardiovascular diseases. The present study proposed to examine Haptoglobin polymorphisms concerning antioxidative enzyme activity in patients with coronary artery disease. MethodsThis case-control inquiry was managed through 398 samples consisting of 225 men and 173 women aged 30–80 who were suspect of CAD. Patients were classified as CAD cases (255) and controls (143). Hp genotyping was conducted using a polymerase chain reaction (PCR). Total antioxidant capacity (TAC) was examined using the Ferric Reducing Ability of Plasma (FRAP) method, and Erythrocyte CAT and GPx activity were measured as antioxidant enzymes. ResultsThe TG, Chol/HDL, diabetes, GPx enzyme, and FRAP results demonstrate a meaningful variation in patients than controls (p > 0.005). The frequency of haptoglobin polymorphisms was significantly different between patients compared to controls. The frequency of Hp genotypes had a significant association with the severity of vascular stenosis so that the Hp2 allele increased the probability of vascular stenosis (P = 0.03).GPx enzyme activity presented a significant difference in Hp2-2 compared to Hp2-1 and Hp1-1 patients. However, there were no notable variations between the Hp genotypes and the amount of catalase and total antioxidant capacity (p > 0.005). ConclusionThis examination confirms that antioxidative enzyme activities are Hp-phenotype-dependent in coronary artery disease. Impaired GPx enzyme activities were prominent among coronary artery disease patients with Hp2-2. Besides, diabetic and high BMI patients with Hp2-2 genotype possess a higher prevalence of coronary artery disease. This study proves the HP2 allele as a genetic determinant in controlling oxidative stress in CAD patients.

Haptoglobin Polymorphisms and Fucosylation Change: Possible Influence of Variation on the Identified Lung Cancer-relevant Biomarkers

Background: Haptoglobin (Hp), an acute-phase protein, is known as a potential diagnostic biomarker in human diseases. Two alleles of Hp (Hp1 and Hp2 ) exist in humans allowing three phenotypes (Hp1-1, Hp2-1, and Hp2-2), which influence the biophysical and biological properties of Hp. Objective: This work aimed to investigate the variation of serum level and fucosylation change among Hp phenotypes in patients with lung cancer compared to healthy donors. Methods: 44 patients with lung cancer and 26 healthy blood donors who lived in the Northern-Thailand region were investigated by the glycoproteomic procedure. Results: The phenotypic distribution of the Hp (Hp1-1:Hp2-1:Hp2-2) in healthy donors was 0.04:0.38:0.58, while the patient group was 0.09:0.52:0.39. The Hp1 allele frequency of patients with lung cancer (0.34) was higher than the healthy donor (0.23). Glycoprotein blotting technique represented that the level of serum Hp and its fucosylation were significantly higher among lung cancer patients compared to those of the healthy donors. However, a downward trend in the fucosylation level from Hp1-1 to Hp2-1, Hp2-2, was seen in the patient group, but varying in the serum Hp level. An N-linked glycan was enzymatically released from discrete Hp multimers of Hp2-1 and Hp2-2 samples. Analysis of glycan profiling by MALDI-TOF-MS showed that reduction of the fucosylated glycan was associated with the size of Hp multimers, resulting in the lower level of fucosylation in Hp2-1 and Hp2-2, respectively. Conclusion: Our finding demonstrates that the Hp phenotype is a dependent risk factor for lung cancer and should be incorporated into further clinical and biochemical investigations of diseases, including lung cancer.

Circulating Biomarkers for the Prediction of Abdominal Aortic Aneurysm Growth.

Background: Abdominal aortic aneurysm represents a distinct group of vascular lesions, in terms of surveillance and treatment. Screening and follow-up of patients via duplex ultrasound has been well established and proposed by current guidelines. However, serum circulating biomarkers could earn a position in individualized patient surveillance, especially in cases of aggressive AAA growth rates. A systematic review was conducted to assess the correlation of AAA expansion rates with serum circulating biomarkers. Methods: A data search of English medical literature was conducted, using PubMed, EMBASE, and CENTRAL, until 7 March 2021, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement (PRISMA) guidelines. Studies reporting on humans, on abdominal aortic aneurysm growth rates and on serum circulating biomarkers were included. No statistical analysis was conducted. Results: A total of 25 studies with 4753 patients were included. Studies were divided in two broad categories: Those reporting on clinically applicable (8 studies) and those reporting on experimental (17 studies) biomarkers. Twenty-three out of 25 studies used duplex ultrasound (DUS) for following patients. Amongst clinically applicable biomarkers, D-dimers, LDL-C, HDL-C, TC, ApoB, and HbA1c were found to bear the most significant association with AAA growth rates. In terms of the experimental biomarkers, PIIINP, osteopontin, tPA, osteopontin, haptoglobin polymorphisms, insulin-like growth factor I, thioredoxin, neutrophil extracellular traps (NETs), and genetic factors, as polymorphisms and microRNAs were positively correlated with increased AAA expansion rates. Conclusion: In the presence of future robust data, specific serum biomarkers could potentially form the basis of an individualized surveillance strategy of patients presenting with increased AAA growth rates.

Influence of the genetic polymorphism of haptoglobin in the occurrence of retinopathy and nephropathy in diabetics subjects

The objective of this study was to determine the frequency of haptoglobin (Hp) genotypes and their association with nephropathy and retinopathy in diabetic subjects. This is a case-control study conducted in diabetic subjects developing nephropathy and/or retinopathy. Each patient was matched to a control of the same sex and the same age ± 2 years. Hp genotyping was performed by conventional PCR without enzymatic digestion on the Proflex® System PCR (Biosystems, Spain) and the biochemical parameters were determined using enzymatic techniques with the Cobas c311 system (Roche Diagnostics, Switzerland). The study population consisted of 60 diabetic subjects with an average age of 56 years and a sex ratio of 0.43. The Hp2-2 genotype was more frequent in diabetic subjects (40%) compared to control subjects (28.3%) (p= 0.18). The distribution of Hp1-1 and Hp2-1 genotypes in diabetic subjects showed rates of 46.7 and 13.3% respectively. Multivariate analysis showed that the Hp 2-2 genotype was more associated with nephropathy (OR=1.77; p=0.8). These results showed an association between Hp polymorphism and diabetic microangiopathy. Thus, Hp2-2 genotype could be associated with a risk factor predisposing to the onset of diabetic kidney disease. Key words: Polymorphism, gene, haptoglobin, diabetes, nephropathy, retinopathy.

Exercise Induced Myoglobinuria is Determined by Haptoglobin Polymorphism.

In professional soccer players (n = 27), confounders of quantitative myoglobinuria following physical training were assessed in order to improve interpretation of post-exercise myoglobinuria. Urine samples were collected in the morning before training sessions, 48 to 72 hours following a game. Urine myoglobin was assayed using immunoturbidimetry. Blood was drawn 48 hours following training session. Creatinine was assayed using a Jaffe method. Creatine kinase (CK) activity was assayed according to the IFCC reference method. Serum myoglobin was assayed using the same assay as the one used for urine. Hp polymorphism was assessed on hemoglobin supplemented serum. Serum Hp concentration was assayed nephelometrically. Training intensity was assessed using a wearable GPS tracking system. Physical load monitoring included the covered total distance, the distance at different speed zones, and the number of sprints/accelerations/decelerations/jumps. Multiple regression analysis was used to detect the determinants of post-exercise myoglobinuria. Myoglobinuria negatively correlated with serum haptoglobin (Hp) concentration. Athletes presented with Hp values, which were lower than the Hp phenotype reference ranges, which can be explained by depletion of circulating Hp stores. Myoglobinuria was most pronounced in players carrying a Hp 2-2 phenotype, which is associated with the lowest Hp reference range. Myoglobin clearance was inversely correlated with Hp 2-2 concentration. Correlation between myoglobinuria and biomarkers of muscle damage was weak. Neither age nor glomerular filtration rate were found to be confounders of myoglobinuria. When comparing myoglobinuria with training intensity, the number of sprints, average acceleration speed, and maximal speed were determining factors for predicting exercise-induced myoglobinuria. In athletes, plasma myoglobin binding capacity is depleted. Moderate myoglobinuria not only should be regarded as a muscle damage marker, but also should be interpreted as an indicator for Hp depletion. Apart from its significance as a biomarker for muscle damage and rhabdomyolysis, myoglobinuria in athletes should be a warning that the heme binding capacity of plasma Hp is depleted, indicating an exhausted defense against Fenton chemistry induced free radicals. Fenton chemistry is associated with free radical formation, which is to be avoided because of the causative relationship with inflammatory processes and tissue damage.

The Role of Haptoglobin Polymorphism in Cardiovascular Disease in the Setting of Diabetes.

Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in individuals with diabetes mellitus (DM). Preclinical models have suggested that excessive oxidative stress and hyperglycemia are directly responsible for this pathological association. However, numerous clinical trials involving the administration of high doses of the antioxidant vitamin E or attempts at strict glycemic control have failed to show a significant reduction of CVD in DM patients. We describe here a possible explanation for the failure of these trials, that being their lack of proper patient selection. The haptoglobin (Hp) genotype is a major determinant of the risk of CVD in the setting of DM. Treatment of individuals with the high-risk Hp genotype with antioxidants or aggressive glycemic control has shown benefit in several small studies. These studies suggest a precision medicine-based approach to preventing diabetes complications. This approach would have a profound effect on the costs of diabetes care and could dramatically reduce morbidity from diabetes.

Effect of Anacetrapib on Cholesterol Efflux Capacity: A Substudy of the DEFINE Trial.

BackgroundAnacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism.Methods and ResultsA total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24‐week follow‐up using J774 macrophages, boron dipyrromethene difluoride–labeled cholesterol, and apolipoprotein B–depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard β, 0.23; 95% CI, 0.05–0.41). This CEC‐raising effect was seen only in men (P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1‐1 haptoglobin genotype (standard β, 0.42; 95% CI, 0.16–0.69) but not the dysfunctional 2‐1/2‐2 genotypes (P interaction=0.02).ConclusionsAmong patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high‐density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.