Existence of HbF Enhancer Haplotypes at<i>HBS1L-MYB</i>Intergenic Region in Transfusion-Dependent Saudi<i>β</i>-Thalassemia Patients

Cyrus, Cyril; Vatte, Chittibabu; Borgio, J. Francis; Al-Rubaish, Abdullah M.; Chathoth, Shahanas; Nasserullah, Zaki; Jarrash, Sana Al; Sulaiman, Ahmed A.; Qutub, Hatem; Alsaleem, Hassan; Alzahrani, Alhusain J.; Steinberg, Martin H.; Ali, Amein K. Al

doi:10.1155/2017/1972429

Cited by 10 publications

(13 citation statements)

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“…The rs2071348 polymorphism on the HBB pseudogene (HBBP1) was previously significantly associated with a milder disease phenotype in Asian β(0)-thalassaemia/haemoglobin E patients [34], but causality due to the rs7482144 marker represented by the Xmn1-HBG2 site has not been fully demonstrated [35]. Detailed analysis of the association of HbF QTL -HBG2 promoter region, BCL11A region, and HMIP region genes on Saudis with various levels of HbA2 revealed that these three SNPs, rs2071348, rs7482144, and rs5006884, were significantly associated with borderline and higher HbA 2 levels in the present study, which are reported as insignificant SNPs for HbF level in Saudis [32] confirming the reciprocal relationship among the HbA 2 and HbF levels [10]. The predominant haplotypes in the borderline and higher HbA 2 cohort consisted of GTC, TCC, and TCT in the HBG2 promoter region comprising the same SNPs: rs2071348, rs7482144, and rs5006884, respectively.…”

Section: Discussioncontrasting

confidence: 59%

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Haemoglobin switching modulator SNPs rs5006884 is associated with increased HbA2 in β-thalassaemia carriers

et al. 2021

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Introduction: Haemoglobin A 2 (HbA 2), the tetramer of αand δ-globin chains, is used as a diagnostic biomarker for β-thalassaemia carriers. The HbA 2 levels are regulated by the presence of HPFH, δ-thalassaemia, HbA 1/2 gene triplication, and variants of KLF1, β-globin gene, and HbF regulating QTLs. Saudi Arabia has a high incidence of borderline HbA 2 levels, thereby making it difficult to classify the haemoglobinopathies. This study aims to investigate the association of known HbF enhancer QTL gene SNPs with HbA 2 levels Material and methods: 14 Specific SNPs in BCL11A, HMIP, OR51B6, HBBP1, and HBG2 loci were genotyped in 164 Saudi β-thalassaemia carriers by TaqMan assay to validate their role as regulators of HbA 2 levels. HbA2 levels were determined using the Variant II β-Thalassemia Short Program Recorder kit. The non-random association of these SNPs was tested using HaploView software. Protein interaction was assessed using 3D structure modelling for OR51B6 (rs5006884), comparative energy minimisation, and root-mean-square deviation (RMSD) prediction. Results: Elevated HbA 2 levels were associated with SNPs in HBBP1, OR51B6, and TCT haplotype from HBG2 promoter region. The bioinformatics modelling and prediction revealed that the exonic rs5006884 had RMSD value deviations and significantly varied binding energy minimisation. α-globin variations were found in 57.92% of individuals but were not associated with elevated HbA 2. Conclusions: The haemoglobin switching modulators rs2071348, rs7482144, and rs5006884 are involved in regulation of HbA 2 level with rs5006884 influencing the tetramer formation. Screening for haemoglobinopathies should take these SNPs into consideration, specifically in borderline HbA 2 cases. Assiduous analysis of rs5006884 as HbA 2 modulator for amelioration of disease severity is recommended.

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Section: Discussioncontrasting

confidence: 59%

“…The effect of rs5006884 on HbF levels was independent of the Xmn1 site, sickle cell haplotype, β-globin gene-like complex, and LCR region. A recent study also showed a lack of association between the rs5006884 SNP with HbF in β-thalassaemia among the Saudi population [32].…”

Section: Discussionmentioning

confidence: 96%

Haemoglobin switching modulator SNPs rs5006884 is associated with increased HbA2 in β-thalassaemia carriers

et al. 2021

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“…The co-inheritance of α-thalassemia has been shown to be an important ameliorating factor in TI cases with either β 0 allele [43] or β + allele [42]. In addition, QTL affecting HbF expression (HBG2, BCL11A and HBS1L-MYB) have been shown to play an important role in ameliorating the thalassemic phenotype [21, 42–45]. In each of the three latter QTL, different SNPs have been studied and revealed different incidences among TI patients representing different ethnic groups [21, 42–45].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, QTL affecting HbF expression (HBG2, BCL11A and HBS1L-MYB) have been shown to play an important role in ameliorating the thalassemic phenotype [21, 42–45]. In each of the three latter QTL, different SNPs have been studied and revealed different incidences among TI patients representing different ethnic groups [21, 42–45]. In a homogenous group of Sardinian β 0 -thalassemic patients, Galenello et al [43] reported that all this group (50 cases of TI and 75 cases of TM) was negative for the XmnI SNP (HBG2) and their mild thalassemic phenotype could be mostly attributed to the co-inheritance of BCL11A, HBS1L-MYB SNPs as well as to α-thalassemia mutations.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of β-thalassemia intermedia in the West Bank, Palestine

Faraon

Daraghmah²,

Samarah

et al. 2019

BMC Hematol

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Background We aimed to investigate the molecular basis of β-Thalassemia intermedia (TI) in the West Bank region and its management practices. Methods This was a case series multi-center study and included 51 cases of TI. DNA sequencing was used to analyze β-globin gene mutations. Common α-globin gene mutations were screened by Gap-PCR (−α 3.7 , −α 4.2 , −- MED , ααα anti3.7 ) or DNA sequencing (α2-IVS II 5 nt del). Xmn I -158 C > T polymorphisms of Gγ-globin gene was determined by RFLP-PCR. Results Seven β-globin gene mutations were observed, namely IVS-I -6 C > T, IVS-I-110 G > A, IVS-II-1 G > A, IVS-I-1 G > A, Codon 37 Trp > Stop, beta − 101 and IVS-II-848 C > A. Ten genotypes were observed. Homozygosity for IVS-I-6 accounted for the majority of TI cases with a frequency of 74.5%. The second common β-globin gene genotype was homozygote IVS-I-110 G > A (5.8%) and homozygote IVS-II-1 G > A (5.8%). The remaining seven genotypes were each detected in about 2% of patients. α-Thalassemia mutations were seen in five patients (9.8%), and included (−α 3.7 , ααα anti3.7 and α2-IVSII-5 nt del). Xmn I polymorphism was observed in four patients (7.8%), three homozygotes and one heterozygote. Conclusions Homozygosity for the mild β-globin gene IVS-I-6 allele was the major contributing factor for the TI phenotype among the study subjects. The role of Xmn I SNP and α-thalassemia mutations in ameliorating the TI phenotype was observed in few patients for each factor. The beta − 101 C > T mutation was diagnosed in one patient in homozygote state for the first time in Palestine.

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“…However, the role of these genetic variants in HbF induction is not fully understood. Multiple studies indicate that the regulatory elements located in this intergenic region are significantly associated with HbF expression (Cyrus et al, ; Wahlberg et al, ). It was reported that β‐thalassemia patients from China who were heterozygous for a 3 bp deletion in their HMIP region are associated with enhanced expression of HbF (Farrell et al, ).…”

Section: Identification Of Molecular Targets For Fetal To Adult Hb Swmentioning

confidence: 99%

Pharmacological and molecular approaches for the treatment of β‐hemoglobin disorders

Lohani

Bhargava

Munshi

et al. 2017

Journal Cellular Physiology

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β-hemoglobin disorders, such as β-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-β (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment. On account of these constraints, reactivation of fetal hemoglobin (HbF) synthesis holds immense promise and is a viable strategy to alleviate the symptoms of β-hemoglobin disorders. Development of new genomic tools has led to the identification of important natural genetic modifiers of hemoglobin switching which include BCL11A, KLF1, HBSIL-MYB, LRF, LSD1, LDB1, histone deacetylases 1 and 2 (HDAC1 and HDAC2). miRNAs are also promising therapeutic targets for development of more effective strategies for the induction of HbF production. Many new small molecule pharmacological inducers of HbF production are already under pre-clinical and clinical development. Furthermore, recent advancements in gene and cell therapy includes targeted genome editing and iPS cell technologies, both of which utilizes a patient's own cells, are emerging as extremely promising approaches for significantly reducing the burden of β-hemoglobin disorders.

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Existence of HbF Enhancer Haplotypes atHBS1L-MYBIntergenic Region in Transfusion-Dependent Saudiβ-Thalassemia Patients

Cited by 10 publications

References 40 publications

Haemoglobin switching modulator SNPs rs5006884 is associated with increased HbA2 in β-thalassaemia carriers

Haemoglobin switching modulator SNPs rs5006884 is associated with increased HbA2 in β-thalassaemia carriers

Molecular characterization of β-thalassemia intermedia in the West Bank, Palestine

Pharmacological and molecular approaches for the treatment of β‐hemoglobin disorders

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