Genomic Variation in the
            <i>MAP3K5</i>
            Gene is Associated with β-Thalassemia Disease Severity and Hydroxyurea Treatment Efficacy

Tafrali, Christina; Paizi, Arsinoi; Borg, Joseph; Radmilovic, Milena; Bartsakoulia, Marina; Giannopoulou, Efstathia; Giannakopoulou, Olga; Stojiljkovic-Petrovic, Maja; Zukić, Branka; Poulas, Konstantinos; Stavrou, Eleana F.; Lambropoulou, Polyxeni; Kourakli, Alexandra; Felice, Alex E.; Papachatzopoulou, Adamantia; Philipsen, Sjaak; Pavlović, Sonja; Georgitsi, Marianthi; Patrinos, George P.

doi:10.2217/pgs.13.31

Cited by 29 publications

(23 citation statements)

References 52 publications

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“…SCD/β-thalassemia compound heterozygous patients were systematically administered HU and characterized as “HU-responders” (plateau HbF levels above 20%) or “HU non-responders” (plateau HbF levels below 20%), based on their HbF expression levels following drug administration. All molecular, hematological, and clinical data of patient cohorts have been described in our previously published work [ 7 , 15 , 17 , 32 , 33 , 40 ]. All tagSNP genotyping samples are of Hellenic origin, collected at the Patras University Hospital (Patras, Greece), AHEPA University Hospital (Thessaloniki, Greece), and Ippokrateio General Hospital of Thessaloniki (Thessaloniki, Greece).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that genomic variants in the MAP3K5 , KLF10 , SIN3A , NOS1 , ARG1 , and ARG2 genes are associated with elevated HbF levels and, hence, milder disease severity in β-type hemoglobinopathy patients and HU treatment response rate in SCD/β-thalassemia compound heterozygous patients [ 4 , 7 , 17 , 40 ]. Herein, we adopted a whole transcriptome analysis of erythroid cells derived from human hematopoietic tissues of various developmental stages to identify candidate genes that are differentially expressed at various developmental stages.…”

Section: Introductionmentioning

confidence: 99%

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Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

et al. 2017

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BackgroundHuman erythropoiesis is characterized by distinct gene expression profiles at various developmental stages. Previous studies suggest that fetal-to-adult hemoglobin switch is regulated by a complex mechanism, in which many key players still remain unknown. Here, we report our findings from whole transcriptome analysis of erythroid cells, isolated from erythroid tissues at various developmental stages in an effort to identify distinct molecular signatures of each erythroid tissue.ResultsFrom our in-depth data analysis, pathway analysis, and text mining, we opted to focus on the VEGFA gene, given its gene expression characteristics. Selected VEGFA genomic variants, identified through linkage disequilibrium analysis, were explored further for their association with elevated fetal hemoglobin levels in β-type hemoglobinopathy patients. Our downstream analysis of non-transfusion-dependent β-thalassemia patients, β-thalassemia major patients, compound heterozygous sickle cell disease/β-thalassemia patients receiving hydroxyurea as fetal hemoglobin augmentation treatment, and non-thalassemic individuals indicated that VEGFA genomic variants were associated with disease severity in β-thalassemia patients and hydroxyurea treatment efficacy in SCD/β-thalassemia compound heterozygous patients.ConclusionsOur findings suggest that VEGFA may act as a modifier gene of human globin gene expression and, at the same time, serve as a genomic biomarker in β-type hemoglobinopathy disease severity and hydroxyurea treatment efficacy.Electronic supplementary materialThe online version of this article (10.1186/s40246-017-0120-8) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

et al. 2017

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“…The very low values of Hb A and Hb F in our patient suggested that they might be more susceptible to sickle cell crisis. Genetic markers that affect the level of HbF in Greek origin patients with Hb S/ β + thal should be studied [10]. …”

Section: Discussionmentioning

confidence: 99%

Successful Outcome of Chronic Intrahepatic Cholestasis in an Adult Patient with Sickle Cell/β⁺Thalassemia

Vlachaki

Andréadis

Neokleous

et al. 2014

Case Reports in Hematology

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Sickle cell/β + thalassemia (Hb S/β +thal) is considered as a variant form of sickle cell disease. Acute episodes of vasoocclusive pain crisis are characteristic for sickle cell disorders and may be complicated by an acute or chronic life-threatening organ dysfunction. Chronic intrahepatic cholestasis is a rare and severe complication in sickle cell disease, characterized by marked hyperbilirubinemia and acute hepatic failure with an often fatal course. Despite the fact that patients with Hb S/β +thal usually have a mild type of disease, herein we describe an interesting case of chronic intrahepatic cholestasis with successful outcome in an adult patient with Hb S/β +thal.

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“…These include phosphodiesterase 7 (PDE7B), mitogen-activated protein kinase kinase kinase 5 (MAP3K5), and peroxisomal biogeneses factor 7 (PEX7) genes with their SNPs showing strong association with different HbF levels [48]. It was shown that a short tandem repeat in the MAP3K5 promoter, as well as intronic variations within both MAP3K5 and PDE7B genes could be associated with lower HbF levels and thus, more severe β-thalassemia phenotype [49]. MAP3K5, encoded by MAP3K5 gene, is a member of the MAPK family and, as such, a part of the MAPK pathway.…”

Section: Hbs1l-myb Intragenic Regionmentioning

confidence: 99%

Novel Therapy Approaches in β-Thalassemia Syndromes — A Role of Genetic Modifiers

Pavlović¹,

Ugrin²,

Stojiljković³

2015

Inherited Hemoglobin Disorders

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The β-thalassemia syndromes are heterogeneous autosomal recessive hereditary disorders, caused by alterations in the HBB gene and characterized by absent or reduced β-globin chain synthesis. The β-thalassemia phenotypes are variable, ranging from severe, transfusion-dependent thalassemia major to mild, asymptomatic thalassemia trait. This interpatient clinical variability has swayed researchers toward identifying genetic modifiers for these disorders. Primary modifiers refer to type of alterations affecting β-globin gene. Secondary modifiers include variations in genes affecting α/β-globin chain equilibrium, such as genes involved in the γ-globin gene expression and genes affecting the amount and stability of α-globin chains. Tertiary modifiers are gene variations affecting the phenotype with regard to the complications caused by β-thalassemia syndromes. A role of secondary genetic modifiers in ameliorating the clinical phenotype has been observed. Secondary genetic modifiers are the most common targets for modern therapy and could be located within α-and γ-globin genes or outside globin gene cluster. The most potent secondary modifier genes are γ-globin genes. Production of fetal hemoglobin (HbF) trough adulthood ameliorates the severity of β-thalassemia phenotype. Large family and genome-wide association studies have shown that regions outside of the β-globin gene cluster are also implicated in γ-globin gene expression regulation. HBS1-MYB intragenic region and BCL11A gene have been particularly studied. Variants within these loci, along with γ-globin gene variants, account for approximately 50% of the HbF level variation, suggesting that additional factors are involved (transcription regulators (KLF1), regulators of α-globin chain stability (AHSP), epigenetic regulators (FoP)). Until recently a definitive cure for β-thalassemia could be achieved with bone marrow transplantation. However, it is available for less than 30% of the patients and bears a significant risk of morbidity and mortality. Alternative strategies, such as gene

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Genomic Variation in the MAP3K5 Gene is Associated with β-Thalassemia Disease Severity and Hydroxyurea Treatment Efficacy

Abstract: Our data suggest that these MAP3K5 variants are indicative of β-thalassemia disease severity and response to HU treatment.

Cited by 29 publications

References 52 publications

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Successful Outcome of Chronic Intrahepatic Cholestasis in an Adult Patient with Sickle Cell/β⁺Thalassemia

Novel Therapy Approaches in β-Thalassemia Syndromes — A Role of Genetic Modifiers

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Genomic Variation in the MAP3K5 Gene is Associated with β-Thalassemia Disease Severity and Hydroxyurea Treatment Efficacy

Abstract: Our data suggest that these MAP3K5 variants are indicative of β-thalassemia disease severity and response to HU treatment.

Cited by 29 publications

References 52 publications

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Successful Outcome of Chronic Intrahepatic Cholestasis in an Adult Patient with Sickle Cell/β+Thalassemia

Novel Therapy Approaches in β-Thalassemia Syndromes — A Role of Genetic Modifiers

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Successful Outcome of Chronic Intrahepatic Cholestasis in an Adult Patient with Sickle Cell/β⁺Thalassemia