Individualizing Fetal Hemoglobin Augmenting Therapy for β-Type Hemoglobinopathies Patients

Gravia, Aikaterini; Chondrou, Vasiliki; Sgourou, Argyro; Papantoni, Ioanna; Borg, Joseph; Κάτσιλα, Θεοδώρα; Papachatzopoulou, Adamantia; Patrinos, George P.

doi:10.2217/pgs.14.101

Cited by 22 publications

(26 citation statements)

References 45 publications

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“…We observed these expected pharmacological effects, regardless the presence of both polymorphisms investigated. Despite patients' response to HC variation be attributed to several single nucleotide polymorphisms (SNPs) in various genes that are linked or not to the β-globin gene cluster [61], we did not observe any HC differential response promoted by the polymorphisms evaluated but both mutations have individually influenced one or other biomarker assessed.…”

Section: Discussioncontrasting

confidence: 71%

Impact of genetic polymorphisms in key enzymes of homocysteine metabolism on the pathophysiology of sickle cell anemia

Silva

Junior

Torres

et al. 2017

Free Radical Biology and Medicine

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This work aimed at studying a possible influence of methylenetetrahydrofolate reductase (MTHFR; c. 677C>T) and cystathionine β-synthase (CBS; 844ins68) polymorphisms on overall oxidative status of sickle cell anemia (SCA) patients and on routine markers, correlating them with hydroxycarbamide (HC) treatment. We evaluated 95 unrelated and diagnosed SCA patients. All patients received a prophylactic treatment with folic acid of 5mg/day, while 41 (43.2%) of them were under hydroxycarbamide (HC) treatment (average dose: 22mg/kg/day). MTHFR and CBS polymorphisms were identified by Polymerase Chain Reaction. Biochemical parameters were measured using spectrophotometric and chromatographic methods. Routine markers were developed by specialized laboratory. We did not find any effect of 677T and "I" allele combination on the biomarkers evaluated. On the other hand, MTHFR 677T mutation was related to a depletion of antioxidant capacity, according to the decreased catalase activity and a reduction about 30% of glutathione levels. Moreover, the presence of the insertion was related to about 23% less biomolecule oxidation levels and lower monocytes count, but about 14% higher lactate dehydrogenase activity. These findings may contribute to highlight that the MTHFR and CBS polymorphisms involvement in SCA pathophysiology is likely to be far more complex than it was explored to date.

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Section: Discussioncontrasting

confidence: 71%

Impact of genetic polymorphisms in key enzymes of homocysteine metabolism on the pathophysiology of sickle cell anemia

Silva

Junior

Torres

et al. 2017

Free Radical Biology and Medicine

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“…It has been proposed that there is a complex interplay between cis-acting elements within the human β-globin gene cluster and transcription factors, such as MYB , BCL11A , KLF1 [ 39 , 41 ], and others, that affect the rate of β-like globin gene transcription. Also, previous studies suggest that genomic loci residing outside the human β-globin gene cluster act as modifier genes to HbF production and are associated with elevated HbF levels and, as such, variable disease severity in β-type hemoglobinopathy patients and HU treatment response rate in SCD/β-thalassemia compound heterozygous patients [ 18 , 25 ].…”

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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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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“…So, it is really fascinating and challenging to explore different dimensions in the branch of pharmacogenomics. There are very few reports so far available for the usefulness of pharmacogenomics in treating thalassemia [29].…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenomics of the Drugs used for the Treatment of Thalassemia

Panja¹,

Basu

2015

J Cytol Histol

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Thalassemia is one of the most prevalent inherited blood disorders all over the world. There are some specific hematologic tests and molecular genetic techniques known for diagnosis of thalassemia. Nowadays, various types of drugs are used for the treatment of thalassemia. Hydroxyurea, Hydroxycarbamide, Deferiprone, Deferisirox, Butyrate and its derivatives are some of the most common and well known drugs which are used for increasing the HbF percentage and iron chelation. Pharmacogenomics is the branch of pharmacology that is associated with the influence of genetic variations on the drug response among patients by correlating genetic variations, expression pattern or single-nucleotide polymorphisms with a drug's efficacy or toxicity. With the help of Pharmacogenomics study "personalized medicine" has been explored, in which drugs and drug combinations are optimized for the genetic makeup of each individual.

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Individualizing Fetal Hemoglobin Augmenting Therapy for β-Type Hemoglobinopathies Patients

Cited by 22 publications

References 45 publications

Impact of genetic polymorphisms in key enzymes of homocysteine metabolism on the pathophysiology of sickle cell anemia

Impact of genetic polymorphisms in key enzymes of homocysteine metabolism on the pathophysiology of sickle cell anemia

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

Pharmacogenomics of the Drugs used for the Treatment of Thalassemia

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