scholarly journals HBG2 -158 (C>T) polymorphism and its contribution to fetal hemoglobin variability in Iraqi Kurds with beta-thalassemia minor

2018 ◽  
Vol 10 (04) ◽  
pp. 370-373
Author(s):  
Dilan J. Albarawi ◽  
Amer A. Balatay ◽  
Nasir Al-Allawi
Keyword(s):  
High Performance ◽  
Fetal Hemoglobin ◽  
Minor Allele ◽  
Beta Thalassemia ◽  
Chromosome 11 ◽  
Hemoglobin Variability ◽  
Thalassemia Minor ◽  
Red Cell Indices ◽  
Different Populations

ABSTRACT PURPOSE: Hemoglobin (Hb) F% is increased in up to half of beta-thalassemia (β-thal) carriers. Several polymorphisms have been linked to such variability in different populations, including HBG2 - 158(C>T) (Xmn I polymorphism) on chromosome 11. To determine the role of this polymorphism in such variability among Iraqi Kurds, the current study was initiated. MATERIALS AND METHODS: A total of 102 consecutive patients diagnosed as β-thal minor were enrolled. The enrollees had their diagnosis based on peripheral blood counts and high-performance liquid chromatography to determine HbA2 and HbF. All enrollees had their DNA extracted by phenol-chloroform method and Xmn I polymorphism detected by restriction fragment length polymorphism-polymerase chain reaction. RESULTS: The mean age (standard deviation [SD]) of the 102 enrollees was 25.4 (14.0) years, and the enrollees included 48 males and 54 females. Xmn I polymorphism was identified in heterozygous state in 46 (45.1%) patients and in homozygous state in one patient (0.98%). Thus, the minor allele frequency of this polymorphism was 0.235 in the studied group. There were no significant differences in red cell indices and HbA2% in carriers of the minor allele compared to noncarriers, while HbF% and absolute HbF concentrations were significantly higher in the former subgroup (P = 0.032 and 0.014, respectively). This polymorphism's contribution to HbF variability was found to be 5.8% in the studied sample. Furthermore, those with HbF ≥2% were 3.2 folds more likely to carry the minor allele. CONCLUSIONS: Xmn I polymorphism is frequently encountered in Iraqi Kurds with β-thal minor, and it is significantly associated with higher fetal hemoglobin in these patients.

scholarly journals Drug repurposing: Hydroxyurea therapy improves the transfusion-free interval in HbE/beta-thalassemia–major patients with Xmn1 polymorphism

2021 ◽  
Author(s):  
Debojoyti Ghosh ◽  
Amrita Panja ◽  
Dipankar Saha ◽  
Uma Banerjee ◽  
Asok Kumar Dutta ◽  
...  
Keyword(s):  
High Performance ◽  
Complete Blood Count ◽  
Drug Repurposing ◽  
Fetal Hemoglobin ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Drug Candidate ◽  
Free Interval ◽  
Pcr Rflp ◽  
Hydroxyurea Therapy

AbstractAimsHbE/β-thalassemia is the prevalent form of severe β-thalassemia in Asian countries. Hydroxyurea (HU) is the most common drug used for the management of sickle-cell anemia but not thalassemia. Here, we aimed to assess clinical HU response among patients with HbE/β-thalassemia with respect to Xmn1 γGglobin polymorphism and elucidate the association between this polymorphism and HU response efficacy.MethodsWe enrolled 49 transfusion-dependent patients with HbE/β-thalassemia. Fetal hemoglobin level was measured using High-performance liquid chromatography (HPLC) and complete blood count was determined pre- and post-HU therapy. Polymerase chain reaction–Restriction fragment length polymorphism (PCR-RFLP) was performed for genotyping Xmn1 γGglobin polymorphism.ResultsA total of 30 (61.22%) patients were found to be responders, whereas the remaining 19 (38.78%) were non-responders. We found 33 patients with heterozygous (C/T) and three with homozygous mutant (T/T) genotype status. We obtained a statistically significant correlation (p < 0.001) between Xmn1 polymorphism and transfusion-free interval. Patients with Xmn1 polymorphism were found to be good responders for HU therapy and showed increased hemoglobin levels.ConclusionsOur findings indicate that HU is a potential drug candidate for thalassemia management, particularly HbE/β-thalassemia. The results hold implications in repurposing HU as an effective and efficient therapy for HbE/β-thalassemia.

Molecular Analysis of Alpha Hemoglobin Stabilizing Protein (AHSP) in Caucasian Patients with different Beta-Thalassemia Phenotypes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3770-3770 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Chiara Refaldi ◽  
Daniela Bignamini ◽  
Laura Zanaboni ◽  
Gemino Fiorelli
Keyword(s):  
High Performance ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Clinical Severity ◽  
Beta Thalassemia ◽  
Red Cell ◽  
Globin Genes ◽  
Nucleotide Polymorphisms ◽  
Thai Population ◽  
Globin Chains

Abstract Beta-thalassemia is a inherited hemoglobin disorder characterized by absent or reduced synthesis of the b globin chains. The pathophysiology and the severity of b-thalassemias reflect the degree of globin chain imbalance and the excess of free a globin chains that precipitate and cause oxidative damage in red cell precursors inducing their premature destruction in the bone marrow (ineffective erythropoiesis). Although the phenotype of b thalassemias can be modified by inherited factors such as different number of a globin genes or increased fetal hemoglobin production, other mechanisms appear to be involved. Recently, a protein, named alpha hemoglobin stabilizing protein (AHSP), that acts as a molecular chaperone specifically for free a globin chains, preventing their precipitation in red cell precursors, has been identified. To establish whether AHSP might have a role in modifying the clinical outcome of b thalassemias, we have analyzed the AHSP gene in 70 Caucasian b thalassaemic subjects: 26 patients with b°/b° genotype (Thalassaemia Major),24 patients with Thalassemia Intermedia (b°/b+ or b+/b+) and 20 patients with a Thalassaemia Intermedia phenotype but with only one mutation in the b globin gene, a normal a globin genotype and no other causes of anemia. In all the subjects, we have performed Denaturing High-Performance Liquid Chromatography (DHPLC) of the three exons and the direct genomic sequencing of coding and noncoding regions (~ 1.5 kb) of AHSP gene. No mutations able to modify the structure or function of AHSP have been found, however we identified eight single nucleotide polymorphisms (SNPs) spanned along the whole gene that segregate in four different aplotypes. To evaluate a possible relationship between a particular aplotype and b thalassemia severity, the allele frequency of each single aplotype in the tree groups has been established and compared to that of 33 Caucasian normal controls: no statistically significant association has been proved. Even though the loss of AHSP aggravates the b thalassaemia phenotype in mice, in Thalassemic Caucasian population the AHSP apparently doesn’t make changes in the clinical severity of b thalassemia confirming the results recently found in Thai population.

scholarly journals Exploring epigenetic and microRNA approaches for γ-globin gene regulation

2021 ◽  
pp. 153537022110281
Author(s):  
Athena Starlard-Davenport ◽  
Ashley Fitzgerald ◽  
Betty S Pace
Keyword(s):  
Gene Regulation ◽  
Globin Gene ◽  
Single Agent ◽  
Unmet Need ◽  
Fetal Hemoglobin ◽  
Therapeutic Interventions ◽  
Globin Genes ◽  
Chromosome 11 ◽  
Globin Gene Regulation

Therapeutic interventions aimed at inducing fetal hemoglobin and reducing the concentration of sickle hemoglobin is an effective approach to ameliorating acute and chronic complications of sickle cell disease, exemplified by the long-term use of hydroxyurea. However, there remains an unmet need for the development of additional safe and effective drugs for single agent or combination therapy for individuals with β-hemoglobinopathies. Regulation of the γ-globin to β-globin switch is achieved by chromatin remodeling at the HBB locus on chromosome 11 and interactions of major DNA binding proteins, such as KLF1 and BCL11A in the proximal promoters of the globin genes. Experimental evidence also supports a role of epigenetic modifications including DNA methylation, histone acetylation/methylation, and microRNA expression in γ-globin gene silencing during development. In this review, we will critically evaluate the role of epigenetic mechanisms in γ-globin gene regulation and discuss data generated in tissue culture, pre-clinical animal models, and clinical trials to support drug development to date. The question remains whether modulation of epigenetic pathways will produce sufficient efficacy and specificity for fetal hemoglobin induction and to what extent targeting these pathways form the basis of prospects for clinical therapy.

Fetal Hemoglobin Expression Is Differentially Affected by Inhibition of the Proposed Dred Complex Constituents, LSD1 and DNMT1

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3263-3263 ◽  
Author(s):  
Tara L Arvedson ◽  
Lynn Tran ◽  
Sandra L Ross ◽  
Sean Yoder ◽  
Alexandra Hertz ◽  
...  
Keyword(s):  
Fetal Hemoglobin ◽  
Erythroid Differentiation ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Hematopoietic Progenitor ◽  
Gamma Globin ◽  
Hbf Induction ◽  
Effect Of Treatment ◽  
Globin Promoter

Abstract Abstract 3263 Introduction Sickle cell disease and beta thalassemia are disorders caused by mutations in adult hemoglobin (HbA) or defects in HbA expression. A potential therapeutic solution is reactivation of fetal hemoglobin (HbF) expression. Although HbF, comprising two alpha and two gamma globin chains, is the primary form of hemoglobin expressed in utero, gamma globin expression is silenced in adults. One proposed mechanism of gamma globin silencing involves binding of the direct repeat erythroid definitive (DRED) repressor complex to sequences in the gamma globin promoter. The DRED complex is reported to include the orphan nuclear hormone receptors TR2 and TR4, lysine specific demethylase (LSD1) and DNA methyltransferase (DNMT1). As both LSD1 and DNMT1 are epigenetic modifiers, gamma globin repression is proposed to be mediated by LSD1- and DNMT1-induced epigenetic changes. To investigate the role of DNMT1 and LSD1 in HbF silencing, HbF expression was evaluated in an erythroid differentiation model where hematopoietic progenitor cells were treated with either DNMT1 or LSD1 small molecule inhibitors or siRNA. Methods Human hematopoietic progenitor cells from healthy donors were induced to become erythroid using a two step protocol including erythropoietin, SCF, IL-3 and hydrocortisone for days 1–7 and erythropoietin and SCF for days 8–14. Cultures were treated with a range of concentrations of either tranylcypromine or S2101 (LSD1 inhibitors) or 5-azacytidine (DNMT1 inhibitor) and compared to HbF-inducing, positive control small molecules pomalidomide and lenalidomide. Cultures were also treated with LSD1 siRNAs and compared to controls. The effect of treatment on gamma, beta and alpha globin transcription was determined by qRT-PCR. The effect of treatment on HbA and HbF levels was determined by ELISA, HPLC, flow cytometry and imaging. Differentiation was characterized by morphology and flow-based detection of CD34 and glycophorin. Effects on viability were characterized by ViCell and flow cytometry. Results Treatment with a concentration range of 5-azacytidine increased the rate of red blood cell differentiation as measured by daily changes in CD34 and glycophorin and hemoglobinization. Quantitative ELISA demonstrated that HbF expression increased two-fold. In contrast, LSD1 inhibition reduced both the rate of proliferation and differentiation of erythroid progenitors. Consistent with impaired differentiation, both beta globin transcription and HbA expression were reduced by up to 84% (qRT-PCR) and 65% (quantitative ELISA), respectively. No increase in gamma globin transcription or HbF expression was observed in response to LSD1 inhibition. Control cultures differentiated as expected: after 14 days of treatment the majority of vehicle-, lenalidomide- or pomalidomide-treated cells were glycophorin-positive and enucleation was readily apparent. Both lenalidomide and pomalidomide treatment induced a two-fold increase in HbF expression, as previously reported. Conclusions Although both LSD1 and DNMT1 are reported to be components of the DRED complex and are proposed to be jointly responsible for epigenetically modifying the gamma globin promoter to silence HbF expression, inhibition of the two proteins had different outcomes on HbF expression. DNMT1 inhibition upregulated HbF expression to a similar extent as pomalidomide (currently in Phase 1 clinical trials for HbF induction), whereas LSD1 inhibition impaired erythroid differentiation and hemoglobinization. These results suggest that the mechanism of gamma globin silencing and the proposed role of the DRED complex require further evaluation. Furthermore, this work also suggests that LSD1 inhibition is not a therapeutic strategy for HbF induction in patients with sickle cell disease or beta thalassemia. Disclosures: Arvedson: Amgen: Employment. Tran:Amgen: Employment. Ross:Amgen: Employment. Yoder:Amgen: Employment. Hertz:Amgen: Employment. Hale:Amgen: Employment. Eschelbach:Amgen: Employment. Dineen:Amgen: Employment. Matyas:Amgen: Employment. Hartley:Amgen: Employment. Morgenstern:Amgen: Employment. Winters:Amgen: Employment. Cindy:Amgen: Employment. Molineux:Amgen: Employment. Coxon:Amgen: Employment.

Role of epoetins in beta-thalassemia minor patients with solid tumors undergoing chemotherapy: Results of a retrospective analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19600-19600
Author(s):  
H. J. Soto Parra ◽  
E. Medula ◽  
F. Latteri ◽  
G. Lavenia ◽  
P. Amadio ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Solid Tumors ◽  
Stage Iv ◽  
Beta Thalassemia ◽  
Second Line ◽  
Mean Values ◽  
Mild Anemia ◽  
Thalassemia Minor ◽  
Prospective Trials

19600 Background: β-Thalassemia minor (β-Tm) is the most common hereditary disorder in the Mediterranean region with a prevalence of 6% in Sicily. β-Tm is characterised by mild anemia (A). Therefore, we performed a retrospective analysis to evaluate the course of A in β-Tm pts with solid tumors (ST) undergoing chemotherapy (CT). Methods: β-Tm pts with ST were identified from our clinical record database [history and/or hemoglobin (Hb) A2 level > 3.3%]. Inclusion criteria were first-line or second-line CT after a CT-free interval of 6 mos. Exclusion criteria:concomitant radiotherapy (RT) , or previous RT to pelvic region, or active bleeding. Results: From July 2004 until the present day, 26 β-Tm pts with ST have been observed, and 23 fulfil the criteria of this analysis. The pt demography was as follows: median age, 56 years (range, 38–76 years); Males: 9 pts; PS 0/1: 19/4; stage IV: 10; types of cancers: breast 7, gastrointestinal 7, others 9; platinum containing regimen: 7. A was evaluated during first and second-line treatments in 19 and 4 pts, respectively. The mean values of Hb and the incidence of pts (%) with mild (from ≥10 and <12 gr/dl) or moderate (<10 gr/dl) A during CT, were as follows. No paradoxical effect of CT on the Hb level was observed. One pt received transfusions (Hb level, 7.8 gr/dl). Nine pts were treated with epoetin (darbepoetin alfa, 7 pts) and iron supplements due to worsening A (mean Hb value = 9 gr/dl ± 0.6): five pts experienced a ≥2 gr/dl increase in the Hb level at 8 weeks, one had >1 gr/dl, one had stable values = 9 gr/dl, and two pts had decreased values, i.e. < 8 gr/dl, and required transfusions. Conclusion: This analysis demonstrates that 70% of β-Tm pts with ST have mild or moderate A prior to CT. The A of β-Tm patients is worsened by CT and results in moderate A in 55% of the pts. Epoetins, particularly effectively ameliorate A when administered to pts with Hb levels of <10 gr/dl. This data suggests that epoetin treatment during CT may benefit β-Tm pts; however, prospective trials are required. No significant financial relationships to disclose. [Table: see text]

scholarly journals Rapid detection of deletions causing delta beta thalassemia and hereditary persistence of fetal hemoglobin by enzymatic amplification

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1673-1682 ◽  
Author(s):  
JE Craig ◽  
RA Barnetson ◽  
J Prior ◽  
JL Raven ◽  
SL Thein
Keyword(s):  
Asian Indian ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Chromosome 11 ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Enzymatic Amplification ◽  
Hereditary Persistence

Abstract A considerable number of deletions of variable size and position that involve the beta-globin gene complex on chromosome 11 are associated with the clinical entities of hereditary persistence of fetal hemoglobin (HPFH) and delta beta thalassemia. Specific deletions appear to be associated with consistent phenotypes and some are known to be recurrent. To facilitate the molecular diagnosis of uncharacterized patients with HPFH and delta beta thalassemia, oligonucleotide primers have been designed to enzymatically amplify deletion-specific products for nine known deletions, which include those responsible for HPFH-1, HPFH-2, HPFH-3, Spanish (delta beta)zero thalassemia, hemoglobin (Hb) Lepore, Sicilian (delta beta)zero thalassemia, Chinese G gamma(A gamma delta beta)zero thalassemia, Asian-Indian inversion-deletion G gamma(A gamma delta beta)zero thalassemia, and Turkish inversion-deletion (delta beta)zero thalassemia. Using this approach, we have successfully characterized the molecular basis for delta beta thalassemia in 23 individuals from 16 families of diverse ethnic origins. Thirteen individuals from this group were shown to be heterozygous for the 13.4- kb Sicilian deletion, two were heterozygous for the 100-kb Chinese G gamma(A gamma delta beta)zero deletion, four were heterozygous for the Turkish form of inversion-deletion delta beta thalassemia, and three were heterozygous for the Asian-Indian form of inversion-deletion G gamma(A gamma delta beta)zero thalassemia. One Vietnamese subject was heterozygous for a 12.6-kb deletion, which we have fully characterized at the molecular level. Sequence analysis of the breakpoint regions of the Chinese deletion and the Turkish rearrangement indicates that, in each case, the mutation is likely to have arisen from a single origin. This hypothesis is supported by the evident geographical clustering of the various deletions described here.

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