Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients

AIM: To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ(IFNL) polymorphisms. METHODS: This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type ofpegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a(Pegaferon#174;) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus(HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes.RESULTS: A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men(92.8%). The most frequent HCV genotype was type-1, infecting 93/152(61.2%) patients. Sustained virologic response(SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2%(52/57) of patients with the IFNL rs12979860 CC genotype and 82.1%(78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT(39/45; 86.7%) and non-TT(61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR(OR = 6.2; 95%CI: 1.2-31.9; P = 0.03).CONCLUSION: The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.     

The early cardiac involvement in patients with β-thalassemia major

BackgroundCardiac complications, heart failure and arrhythmias remain the major causes of death in thalassemia major.AimTo detect the early cardiac involvement in β-thalassemic patients.Patients and methods56 Patients (pts) with β-thalassemia major and transfusion burden ?12 times/year (age 6–16 years) were included in our study, classified into three groups according to serum ferritin, group I: 21 pts with ferritin level <2500 ng/ml, group II: 23 pts with ferritin level 2500–5000 and group III: 12 pts with ferritin level >5000 ng/ml. They were subjected to detailed clinical evaluation, routine laboratory investigations, serum ferritin level, ECG {corrected QT intervals (QTc) and QT dispersion(QTd)}, echocardiography for measurement of left atrial (LA) active emptying fraction, Systolic (peak systolic wave, Q–S peak duration) and diastolic functions of left ventricle using standard and tissue Doppler imaging (TDI).ResultsGroups III and II showed a significant increase in LV septal and posterior wall thickness than group I while QTc and QTd were increased significantly only in group III compared to group I (P = 0.00, 0.01). LV diastolic function and LA active emptying fraction were significantly impaired in group III and II compared to group I while LV systolic function parameters by TDI were impaired significantly in group III compared to group I with insignificant difference by standard echocardiography.ConclusionThe increase in LV septal and posterior wall thickness precedes ECG changes. Also LV diastolic dysfunction and impaired LA active emptying fraction precede LV systolic dysfunction.     

Clinicopathological and radiological study of Egyptian β-thalassemia intermedia and β-thalassemia major patients: relation to complications and response to therapy

The clinico epidemiological characteristics, frequency of complications, and response to various therapeutic modalities in 80 Egyptian β-thalassemia intermedia (β-TI) patients were compared with 70 β-thalassemia major (β-TM) patients. β-Thalassemia intermedia patients had a higher incidence of left atrium dilatation, right ventricular dilatation and pulmonary hypertension, whereas, β-TM patients showed a higher incidence of left ventricular (LV) dilatation, restrictive LV filling and impaired LV contractility, with an overall higher incidence of heart disease (p <0.001). Short stature, delayed puberty, osteoporosis, bone fractures, diabetes mellitus and viral hepatitis was frequently observed in β-TM patients compared with β-TI patients (p <0.05). Administration of hydroxyurea (HU) alone was associated with significant improvement in hematological parameters and quality of life for β-TI patients. In conclusion, the risk of complications still burdens the life of Egyptian thalassemia patients and their frequency varies between β-TI and β-TM. We provide evidence that calls for the use of HU in β-TI patients.     

Comparative study of pulmonary circulation and myocardial function in patients with β-thalassemia intermedia with and without hydroxyurea, a case-control study

Objectives: To compare myocardial systolic and diastolic functions and pulmonary circulation by two‐dimensional, M‐mode, Doppler, and pulsed tissue Doppler imaging in patients with β‐thalassemia intermedia who received hydroxyurea at least for 1 yr, patients who did not receive hydroxyurea, and a healthy control group. Methods: We assigned 84 patients with thalassemia intermedia into two groups: one of two was treated with hydroxyurea for at least 1 yr and no hydroxyurea. M‐mode echocardiographic, Doppler, and pulsed Doppler tissue images were compared in these two groups and in 20 control participants who did not have thalassemia. For the estimation of pulmonary hypertension, pulmonary acceleration time below 100 ms was considered as an index of pulmonary hypertension. Results: There were no significant differences in M‐mode echocardiographic findings between three groups. Doppler echocardiography detected no significant differences between the treated and untreated groups. In treated hydroxyurea group, 11.7% patients had pulmonary acceleration time below 100 ms and in untreated group 21% (LR = 1.45, P = 0.22). Pulsed Doppler tissue imaging parameters did not differ significantly between treated and untreated patients (P > 0.05). Pulsed Doppler tissue images showed significant changes between patients and controls in peak systolic velocity of the septum, peak atrial velocity of the septum (Aas), the peak systolic velocity of the tricuspid valve (St), the peak early diastolic velocity of the tricuspid valve (Eat), and the peak late diastolic velocity of the tricuspid valve (Aat). Conclusion:  This study revealed that in spite of decrease in estimated pulmonary hypertension in treated group, HU has no statistically significant effect on pulmonary acceleration time and M‐mode, Doppler, and tissue Doppler changes of patients with TI.     

Erythrocytic phosphatidylserine exposure and hemostatic alterations in β-thalassemia intermediate patients

Introduction

Hypercoagulable state is one of the common findings in beta-thalassemia intermedia (β-TI), particularly in splenectomized patients, with infrequent blood transfusion. Abnormality of the red blood cells (RBC) membrane due to oxidative damage is suggestive of possible etiologies. Membrane lipid peroxidation increases the exposure of phosphatidylserine (PS) that plays a role in the activation of coagulation factors V and X, subsequently initiating thrombosis. Our aim of this study was to find the probable correlation of the alteration of the PS on the RBC outer membrane with the hypercoagulable state in the β-TI patients.

Materials and methods

Our cross-sectional study was conducted on 39 splenectomized β-TI patients and 38 age-matched healthy controls. The mean age was 37 years. Analysis of the PS exposure on the RBCs was performed by fluorescein isothiocyanate (FITC) conjugated AV protein .Measurement of the coagulation factors X, V and antithrombin III (AT-III) was performed. We also checked the D-dimer levels .Analysis was performed by SPSS16.

Results

Fluorescence of FITC-Annexin V labeling on patients RBCs were higher than healthy controls; (2.8 ± 2.2%) of the patients versus (0.4 ± 0.18%) in the control group and was statistically significant (P < 0.05). Mean levels of factor X and AT-III of the patients as compared with the control group decreased and showed significant difference (P < 0.05).

Conclusions

Circulation of thalassemic RBCs, which abnormally possess PS on RBC membrane outer surface, suggests the possibility of the gradual consumption of the coagulation factors in the presence of a chronic coagulability state.     

The β2-adrenoreceptor gene promoter polymorphisms may modulate β2-agonist- and glucocorticoid-induced IgE synthesis

Backgroundβ2-adrenoreceptor (β2-AR) agonists and glucocorticoids (GCS) were shown to induce IgE synthesis in human PBMCs. Serum total IgE levels are associated with single nucleotide polymorphisms (SNPs) of the β2-AR gene. We aimed to assess the association of the effect of fenoterol (β2-AR agonist) on IL-4-driven and budesonide-induced IgE synthesis with genetic variants of β2-AR.MethodsThe study included 25 individuals: 13 with allergic asthma and/or allergic rhinitis and 12 healthy volunteers. PBMCs were cultured with IL-4, fenoterol and/or budesonide, and IgE concentrations in supernatants were assessed. Five SNPs in positions: −47, −20, 46, 79 and 252 of β2-AR were determined by direct DNA sequencing.ResultsIn −47 T/T and −20 T/T patients, incubation with fenoterol resulted in decreased IgE production, whereas in −47 C/T and −47 C/C as well as in −20 C/T and −20 C/C individuals, it was enhanced. In contrast to fenoterol, budesonide-induced IgE synthesis was significantly increased in −47 T/T and −20 T/T patients as compared to −47 C/T, −47 C/C, −20 C/T and −47 C/C individuals. Polymorphisms in positions 46, 79 and 252 were not associated with fenoterol- or budesonide-modulated IgE synthesis. No differences in the distribution of IgE synthesis was seen between atopic and non-atopic individuals carrying the same alleles.ConclusionsThe differential effect of β2-agonists and GCS on IgE synthesis may be associated with genetic variants of promoter region of the β2-AR gene.     

Genotype–phenotype relationship of patients with β-thalassemia taking hydroxyurea: a 13-year experience in Iran

We evaluated the clinical responses to hydroxyurea (HU), adverse effects, and β-globin gene variants in a large series of β-thalassemic patients over a 13-year period in Iran. The patients (n = 232) were divided into two groups: transfusion-dependent β-thalassemia patients 2 years of age and older (n = 126; Group 1), and β-thalassemia intermedia (βTI) patients without any history of blood transfusion or with a long-interval transfusion (n = 106; Group 2). In Group 1, 86 patients became transfusion-free, and 25 patients needed 1–2 transfusions per year at the end of study. All except three patients in Group 2 were completely transfusion free with a significant increase in Hb level after 1 year compared to the baseline Hb value (P < 0.0001). We did not find a significant correlation of response to HU with XmnI polymorphism or IVS II-I (G > A) mutation (P > 0.05). In our study, HU at a dose of 8–15 mg/kg/day was effective in decreasing or effecting cessation of the need for regular blood transfusion, as well as in increasing Hb levels in β-thalassemia patients, without any major side effects. Hydroxyurea may thus represent a safe alternative to blood transfusion in transfusion-dependent β-thalassemia patients, or help to increase Hb level in untransfused βTI patients.     

Hepatitis C in patients with β-thalassemia major. A single-centre experience

Chronic hepatitis C (CHC) and iron overload are the main causes of liver disease in β-thalassemia major (βTM). There is limited data regarding the course of CHC in this population. All patients (n?=?144) from the thalassemia centre of the University Hospital of Patras were evaluated (January 1981 to June 2012). Patients were classified into group A (n?=?57), which consisted of patients with CHC, who either had received antiviral treatment (n?=?49) or not (n?=?8), and group B which included 87 patients without CHC. Nineteen patients died during follow-up (median: 257.5 months (1–355)). Survival rates were 84.2 % and 88.5 % for group A and B, respectively. The causes of death were heart failure (63.2 %), accident (10.5 %), sepsis (5.3 %), liver failure (5.3 %), hepatocellular carcinoma (HCC) (5.3 %), non-Hodgkin lymphoma (5.3 %) and multiorgan failure (5.3 %). There were no differences in total survival between the two groups (p?=?0.524). In the multivariate analysis, survival was neither correlated with CHC (p?=?ns), nor with anti-HCV treatment (p?=?ns), whereas independent negative predictors were presence of heart failure (p?<?0.001), presence of malignancy other than HCC (p?=?0.001) and non-adherence to chelation treatment (p?=?0.013). Predictive factors for the development of cirrhosis were: CHC (p?<?0.001), age?>?35 years (p?=?0.007), siderosis grade 3/4 (p?=?0.029) and splenectomy (p?=?0.001); however, multivariately, only siderosis grade 3/4 was found to be significant (p?=?0.049). In this study, survival of patients with βTM was mainly associated with heart failure, presence of malignancy other than HCC and non-adherence to chelation treatment, rather than with liver disease. Multicentre studies need to be designed to define more accurately the indications of antiviral treatment in this population.     

Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia

To evaluate the association between fetal hemoglobin (HbF) levels and morbidity in β-thalassemia intermedia (TI), we analyzed data from 63 untransfused patients who had also never received HbF induction therapy. Patient records were reviewed for any history of 10 predefined morbidities. Laboratory measurements for markers of ineffective erythropoiesis were also obtained. The mean age of patients was 32.1 years, 47.6% were males, and the median HbF level was 37.2%. HbF levels correlated positively with total hemoglobin, yet negatively with growth differentiation factor-15 and non-transferrin-bound iron levels. Median HbF levels were significantly lower in patients with the majority of evaluated morbidities than in those without. There was a strong negative adjusted linear correlation between the HbF level and the total number of morbidities (R(2) = 0.825, P < .001). The HbF threshold of 63.7% had 95.5% sensitivity and 100% specificity for ensuring absence of morbidity. There exists a strong association between HbF levels and morbidity in the subset of untransfused patients with TI.     

Single nucleotide polymorphisms of the genes encoding IL-10 and TGF-β1 in Iranian children with atopic dermatitis

Background

Atopic dermatitis is an inflammatory skin disease in which both genetic and environmental factors interact to determine the susceptibility and severity of the disease.

Variants in genetic modifiers of β-thalassemia can help to predict the major or intermedia type of the disease

A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) β-thalassemia mutations; (ii) the XmnI SNP; (iii) the -3.7 kb α-thal deletion; (iv) the tag-SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L-cMYB inter-region. Multivariate analysis was performed to study the risk of thalassemia Intermedia phenotype associated with the different combinations of alleles. The presence or absence of the favorable alleles could accurately predict the type of thalassemia in 83.2% of the cases. The percentage of correct predictions made from the β-thalassemia mutations and the XmnI SNP alone were significantly improved by the adjustment with the 3 other modifiers; from 73.6% to 83.2% (P<0.001). In this study, we showed that predictions based on genetic modifiers can foresee the Major or Intermedia type of β-thalassemia, even in cohorts of patients with various β-globin genotypes.     

BCL11A Down-Regulation Induces γ-Globin in Human β-Thalassemia Major Erythroid Cells

Abstract

Fetal hemoglobin (Hb F, α2γ2) is a potent genetic modifier of the severity of β-thalassemia (β-thal) and sickle cell anemia. Differences in the levels of HbF that persist into adulthood affect the severity of sickle cell disease and the β-thal syndromes. B-cell lymphoma 11?A (BCL11A) is a potent silencer of HbF. Here, we reactivated γ-globin expression by down-regulating BCL11A to alleviate anemia in the β-thal major (β-TM) patients. BCL11A were down-regulated by lentiviral RNAi (RNA interference) in the K562 cell line and an in vitro culture model of human erythropoiesis in which erythroblasts are derived from the normal donor mononuclear cells (MNC) or β-TM MNC. The expression of γ-globin were analyzed by qPCR (quantitative real-time polymerase chain reaction) and Western blot techniques. Our data showed that down-regulation of BCL11A induces γ-globin production in the K562 cell line and human erythrocytes from normal donors and β-TM donors, without altering erythroid maturation. This is the first report on γ-globin induction by down-regulation of BCL11A in human erythroblasts derived from β-TM.     

Association between NOD2 single nucleotide polymorphisms and Grade III–IV acute graft-versus-host disease: A meta-analysis

Abstract

Objectives

The effects of NOD2 single nucleotide polymorphisms (SNPs) on Grade III–IV acute graft-versus-host disease (aGVHD) risk are somewhat contradictory in different studies. The aim of the meta-analysis was to clarify the effects of NOD2 SNPs on the incidence of Grade III–IV aGVHD.

Methods

We searched PubMed, EMBASE, Web of SCIENCE, WanFang and Chinese National Knowledge Infrastructure (CNKI) databases to collect eligible publications. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between NOD2 polymorphisms and Grade III–IV aGVHD risk.

Results

A total of nine studies from eight publications met the inclusion criteria and were included in this meta-analysis. Patient NOD2 SNPs were not associated with aGVHD risk. A tendency of higher risk to develop Grade III–IV aGVHD was found in patients with pairs NOD2 SNPs. Subgroup analyses showed that pairs NOD2 SNPs were associated with Grade III–IV aGVHD in the Caucasian population and in identical sibling donors (IS), but not in matched unrelated donors (MUD). In patients who received hematopoietic stem cell transplantation (HSCT) with T-cell depletion and gut decontamination, there was still an association between pairs NOD2 SNPs and Grade III–IV aGVHD risk.

Conclusions

Our meta-analysis suggests that pairs NOD2 SNPs, not patient NOD2 SNPs, may be associated with Grade III–IV aGVHD risk, especially in the Caucasian population. It is also indicated that in pairs NOD2 polymorphisms group, patients who receive HSCT from IS may experience higher risk of Grade III–IV aGVHD.     

Inverse correlation of plasma leptin and soluble transferrin receptor levels in β-thalassemia patients

The aim of the study was to investigate the association of leptin with hematological parameters in beta-thalassemia patients in Greece. We measured plasma levels of soluble transferrin receptor (sTfR) and leptin by enzyme-linked immunosorbent assay (ELISA) in 40 beta-thalassemia patients (21 transfusion dependent and 19 not transfused or sporadically transfused), in 20 beta-thalassemia carriers, and in 30 healthy individuals (HI). The percentage of reticulocytes (RET) was measured by the NE 9500 Sysmex automated method. Body mass index (BMI) was calculated by dividing body weight (kg) by square height (m). Endocrine measurements including sex hormones were also determined. sTfR concentrations were significantly higher in both transfusion-dependent (females 10.5+/-2.9, males 9.1+/-3.1) and non-transfusion-dependent patients (females 15.8+/-5.4, males 19.8+/-13.7) as compared to carriers (females 3.1+/-2.5, males 3.8+/-1.8) and to HI (females 1.5+/-1.2, males 2.5+/-2.1). Leptin levels were lower both in female and in male transfusion-dependent patients (0.5+/-0.3 and 1.2+/-1, respectively) and in non-transfused males (1.9+/-2) compared to carriers (females 7.9+/-2.7, males 13.1+/-9.1) and HI (females 14.6+/-6, males 7.5+/-3). There was a negative correlation between leptin and sTfR levels in transfused patients (R=-0.61, p<0.05). A stronger negative correlation (R=-0.7, p=0.006) was found in hypogonadic men and women with beta-thalassemia. These findings enhance previous results indicating that leptin may play some role in hematopoiesis and could associate the pathophysiology of thalassemic patients with the triggering effect of leptin in reproductive ability.