De novo Origination Patterns of the Malaria-resistant, Sickle-cell-anemia-causing Hemoglobin S Mutation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA717070 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:De novo Origination Patterns of the Malaria-resistant, Sickle-cell-anemia-causing Hemoglobin S Mutation
| PRJNA717071 | ENA
Project description:The heterozygous inheritance of the sickle cell gene, called sickle cell trait (HbAS), was previously thought to be benign. HbAS is now associated with an increased risk for chronic kidney disease, pulmonary embolisms, and exertional rhabdomyolysis. The role of gene expression, as regulated by microRNAs, in these clinical HbAS associations has not been investigated. We explored the association between HbAS and the differential expression of circultaing (plasma) microRNAs when compared to the normal hemoglobin phenotype (HbAA). In stark contrast, the homozygous inheritance of the sickle cell gene, called sickle cell anemia (HbSS) is a severe disease that was previously associated with early mortality and severe morbidity. With appropriate care and early interventions, people with HbSS have improved life expectancy but still experience significant morbidity including cardiac, kidney, and pulmonary disease. The role of gene expression as regulated by microRNA in these clinical HbSS associations has not been investigated. We also explored whether the presence of HbSS is associated with the differential expression of circultaing (plasma) microRNAs as compared to the normal hemoglobin phenotype (HbAA).
2025-03-22 | GSE285580 | GEO
Project description:We hypothesized that miRNA regulation may be invloved in hydroxyurea-mediated fetal hemoglobin induction. Microarray analysis was utilized as an initial screening tool to determine differential miRNA expression in CD71+ erythroid cells comparing cells from control individuals without sickle cell anemia to patients with sickle cell anemia prior to treatment with hydroxyurea and patients receiving the maximum tolerated dose (MTD) of hydroxurea.
2011-11-21 | GSE32035 | GEO
Project description:We hypothesized that miRNA regulation may be invloved in hydroxyurea-mediated fetal hemoglobin induction. Microarray analysis was utilized as an initial screening tool to determine differential miRNA expression in CD71+ erythroid cells comparing cells from control individuals without sickle cell anemia to patients with sickle cell anemia prior to treatment with hydroxyurea and patients receiving the maximum tolerated dose (MTD) of hydroxurea. CD71+ cells were isolated from whole blood of control individuals (n=2), pediatric patients without hydroxyurea treatment (n=3) and pediatric patients at hydroxyurea MTD (n=3). All 8 samples were analyzed for miRNA expression.
2011-11-21 | E-GEOD-32035 | biostudies-arrayexpress
Project description:Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. However, pharmacologic induction of fetal hemoglobin sufficient to diminish clinical severity in sickle patients has been challenging. We recently found that up-regulation of PGC-1α can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecular compound SR-18292 increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells or β-YAC and sickle cell disease mice. Sickled red blood cells are significantly reduced and disease complications are alleviated in SR-18292-treated sickle mice. SR-18292, or agents in its class, could be a promising therapeutic for sickle cell disease.
2024-08-08 | GSE256494 | GEO
Project description:Sickle cell disease (SCD) results from a point mutation in the β-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)–like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cell–derived erythroid progenitors. We investigated the ability of dimethyl fumarate (DMF), a small-molecule Nrf2 agonist, to activate γ-globin transcription and enhance HbF in tissue culture, murine and primate models. DMF recruited Nrf2 to the γ-globin promoters and the locus control region of the β-globin locus in erythroleukemia cells, elevated HbF in SCD donor–derived erythroid progenitors, and reduced hypoxia-induced sickling. Chronic DMF administration in SCD mice induced HbF and increased Nrf2-dependent genes to detoxify heme and limit inflammation. This improved hematological parameters, reduced plasma-free Hb, and attenuated inflammatory markers. Chronic DMF administration to nonanemic primates increased γ-globin mRNA in BM and HbF protein in red cells. DMF represents a potential therapy for SCD to induce HbF and augment vasoprotection and heme detoxification
2017-11-01 | GSE105035 | GEO
Project description:The Differential Expression of Circulating MicroRNAs in Sickle Cell Trait and Sickle Cell Anemia compared to the Normal Hemoglobin Phenotype.
| PRJNA1204922 | ENA
Project description:Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease
| PRJNA414450 | ENA
Project description:<p>Phenotypic heterogeneity is characteristic of sickle cell anemia, a Mendelian disorder caused by homozygosity for the sickle HBB gene (glu6val). Patients have different rates of hemolysis/vasculopathy and viscosity/vasoocclusion-related complications. These complications account for a substantial reduction in life expectancy. In 1994, the median life expectancy for men and women with sickle cell anemia was 42 and 48 years, respectively, and despite many advances in care, the annual mortality still approaches 4%. Fetal hemoglobin (HbF) is one of the most studied markers of severity of sickle cell anemia, and detailed longitudinal measurements were taken on subjects enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cubic root transformation of the median values from follow-up in 848 African American subjects is the phenotype data used in the GWAS of fetal hemoglobin. The analysis was adjusted by sex. Details are in Solovieff et al., Blood 2010 [PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20018918" target="_blank">20018918</a>].</p> <p>To integrate individual disease complications into a comprehensive measure of severity, we developed a model of the associations among clinical and laboratory variables that scored disease severity as the risk of death within 5 years. This network was developed using data obtained from more than 3,400 subjects from the CSSCD, and its accuracy was validated in two unrelated sets of sickle cell patients. Recently, the network was also validated in a small European cohort of patients with sickle cell anemia. We used extreme values of disease severity as cases and control in the GWAS of severity of sickle cell anemia. We conducted the GWAS in 1,265 patients with either "severe" (177) or "mild" disease (1088) based on a network model of disease severity. Details are in Sebastiani et al. Am J Hematol, 2010 [PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20029952" target="_blank">20029952</a>].</p>
| phs000366.v1.p1 | EGA
Project description:Sickle cell disease (SCD) is caused by a pathogenic hemoglobin (Hb) mutation, yet patients can have dramatically variable clinical manifestations. Here we address the genetic basis of this clinical heterogeneity. Using a systems genetics approach, we performed whole blood gene expression analysis and eQTL analysis on different clinical phenotypes in SCD patients. We generated whole blood gene expression profiles for 311 West-African children recruited from the National Sickle Cell Disease Centre in Cotonou, Benin which included 250 patients with varying degrees of SCD severities and 61 age-matched controls. SCD is caused by a point-mutation in the beta-hemoglobin gene that changes the normal HbAA protein into, most often, an abnormal HbSS or HbSC protein. The SCD patients recruited in the study either had HbSS or HbSC phenotypes and were categorized into different 3 clinical states based on follow-up status (Rahimy, MC, et al. Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in sub-Saharan African setting. Bood 102, 834-838. 2002). When patients are refered to the clinic, they are enrolled when they are in steady-state condition, and are labeled as entry (E). Patients followed at the SCD clinic are labeled as FU. Control patients were recruited and are labeled as C. Patients were also assigned a severity score (Sebastiani, P. et al. A network model to predict the risk of death in sickle cell disease. Blood 110, 2727-2735, 2007). Hemoglobin protein status (Hb phenotype) was confirmed for each patient using standard electrophoretic techniques. We generated genotypes for 263 of these individuals and performed principal component analysis (PCA) which identified 2 signigicant genotypic principal components (gPC1 and gPC2). Using the gene expression and genotyping data, we performed an eSNP analysis. . Gene expression data presented in this study.
2014-07-01 | E-GEOD-35007 | biostudies-arrayexpress