Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study

Κολλιοπούλου, Αλεξάνδρα; Siamoglou, Stavroula; John, Anne; Sgourou, Argyro; Kourakli, Alexandra; Symeonidis, Argiris; Vlachaki, Efthymia; Chalkia, Panagiota; Theodoridou, Stamatia; Ali, Bassam R.; Κάτσιλα, Θεοδώρα; Patrinos, George P.; Papachatzopoulou, Adamantia

doi:10.1080/03630269.2019.1597732

Cited by 8 publications

(9 citation statements)

References 39 publications

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“…The FLT1 variant rs2182008 (G>A) is associated with elevated HbF levels ( p = 0.039) among non-transfusion-dependent (NTDT) Hellenic-origin β –thalassemia patients (n = 7). This suggests that rs2182008 is a potential biomarker for predicting β –thalassemia severity, since patients with the effect allele exhibit a mild phenotype and have a reduced dependency on blood transfusions [ 50 ].…”

Section: Factors Involved In the Transcription Control Of The Hbb Locusmentioning

confidence: 99%

“…ARG2 is associated with HU therapy response in β –thalassemia patients. In a comparison between healthy subjects (n = 53) and NTDT β –thalassemia patients (n = 7), ARG2 variant rs10483801 was significantly associated with elevated HbF levels ( p = 0.001), suggesting that ARG2 may be a predictor for a mild β –thalassemia phenotype [ 50 ].…”

Section: Genetic Findingsmentioning

confidence: 99%

“…In erythroid cell maturation, NOS2A gene expression decreases along with a decrease of γ–globin, reducing the formation of HbF. Upon HU therapy in HbS (HBB: c.20A>T)– β –thalassemia compound heterozygous patients (n = 42), the NOS2A rs944725 variant was associated with an increase in HbF ( p = 0.015), indicating that NOS2A gene expression may be another marker for a positive response to HU therapy [ 50 ].…”

Section: Genetic Findingsmentioning

confidence: 99%

“…The presence of an extra GCGCG repeat may decrease MAP3K5 gene expression, possibly by disruption of the p38 and JNK MAPK pathway, consequently leading to the absence of response to HU treatment. This suggests that MAP3K5 gene expression is an indicator of HU therapy response [ 50 ]. Furthermore, a short tandem repeat in the MAP3K5 promoter and two intronic MAP3K5 gene variants (rs9483947 and rs9376230) were analyzed in β –thalassemia major (n = 92), β –thalassemia minor (n = 11), and healthy controls (n = 94).…”

Section: Genetic Findingsmentioning

confidence: 99%

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Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

et al. 2021

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Thalassemia, an inherited quantitative globin disorder, consists of two types, α– and β–thalassemia. β–thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the β–globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases β–globin expression. Down-regulation of γ–globin suppressor genes, i.e., BCL11A, KLF1, HBG-XMN1, HBS1L-MYB, and SOX6, elevates the HbF level. β–thalassemia severity is predictable through FLT1, ARG2, NOS2A, and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the β–thalassemia patient’s response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1, PRDX2, TRX1, and SOD1, to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single β–thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of β–thalassemia with α–thalassemia ameliorates the β–thalassemia clinical presentation. In conclusion, the management of β–thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future.

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Section: Factors Involved In the Transcription Control Of The Hbb Locusmentioning

confidence: 99%

Section: Genetic Findingsmentioning

confidence: 99%

Section: Genetic Findingsmentioning

confidence: 99%

Section: Genetic Findingsmentioning

confidence: 99%

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Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

et al. 2021

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“…In this study, 87 participants of Greek descent were recruited with different phenotype severity (from moderate to severe) and interestingly, the majority of results remained statistically significant. According to the authors, the rs9376230, rs944725, and rs10483801 variants located in the MAP3K5 , NOS2A , ARG2 genes were considered as potential pharmacogenomic biomarkers, and subsequently, FLT1 (rs2182008) and ARG2 (rs10483801) genes were significantly associated with HbF levels and disease severity, respectively [ 69 ]. Furthermore, two independent research studies strongly suggest that the rs3191333 tag-SNP in the 3′-UTR of the KLF10 gene is involved in HbF production and must be assessed as a discrimination marker between responders and non-responders to HU treatment, on β-type hemoglobinopathies [ 70 , 71 ].…”

Section: Genome-guided Treatment: Pharmacogenomics For β-Type Hemoglobinopathiesmentioning

confidence: 99%

Genome-based therapeutic interventions for β-type hemoglobinopathies

et al. 2021

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For decades, various strategies have been proposed to solve the enigma of hemoglobinopathies, especially severe cases. However, most of them seem to be lagging in terms of effectiveness and safety. So far, the most prevalent and promising treatment options for patients with β-types hemoglobinopathies, among others, predominantly include drug treatment and gene therapy. Despite the significant improvements of such interventions to the patient’s quality of life, a variable response has been demonstrated among different groups of patients and populations. This is essentially due to the complexity of the disease and other genetic factors. In recent years, a more in-depth understanding of the molecular basis of the β-type hemoglobinopathies has led to significant upgrades to the current technologies, as well as the addition of new ones attempting to elucidate these barriers. Therefore, the purpose of this article is to shed light on pharmacogenomics, gene addition, and genome editing technologies, and consequently, their potential use as direct and indirect genome-based interventions, in different strategies, referring to drug and gene therapy. Furthermore, all the latest progress, updates, and scientific achievements for patients with β-type hemoglobinopathies will be described in detail.

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Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent β-thalassemia: a comprehensive single-center experience

et al. 2021

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Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study

Cited by 8 publications

References 39 publications

Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

Genome-based therapeutic interventions for β-type hemoglobinopathies

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent β-thalassemia: a comprehensive single-center experience

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