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Cell Journal، جلد ۱۳، شماره Supplement، صفحات ۰-۰
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عنوان انگلیسی I-4: Genetic Modifiers in Beta-Thalassemia
چکیده انگلیسی مقاله Thalassemia diseases, both α-and β-thalassemias, are clinically variable. Although the molecular defect of most thalassemia is known, the severity of the patients who have seemingly identical genotypes can vary greatly. It is necessary to understand the “genotype-phenotype” interaction in order to get better understanding of disease severity to provide better care for the patients. Betathalassemia/ Hb E is one of the most common monogenic diseases in Southeast Asia. Clinically patients show remarkable disease heterogeneity, varying from nearly asymptomatic to severe transfusion-dependent disease in which the patients die within the first decade of life. It is believed that a number of genetic factors modifying disease severity may account for this variability. The clinically 235 mild and 383 severe β-thalassemia/Hb E patients were selected using a validated scoring system for thalassemia severities, after exclusion of co-inherited α- and β+-thalassemias. In searching for genetic factors modifying the disease severity, genotyping of SNPs was conducted with the Illumina Human 610-Quad BeadChips array. An independent cohort of 52 mild and 122 severe cases from Indonesia were also recruited for the replication study. Twenty-three SNPs in 3 independent genes were identified to be significantly associated with the disease severity. The highest association was observed with SNPs on the β-globin gene cluster (chr.11p15). The others were the intergenic region between the HBS1L and MYB genes (chr.6q23) and the BCL11A gene (chr.2p16.1). All three loci were replicated in the Indonesian patient cohort. Association to the fetal hemoglobin level was also observed with SNPs on these three regions. Our data indicated that several genetic loci act in concert to influence Hb F levels of β0- thalassemia/Hb E patients. Gene expression profiles of erythroid precursor cells (EPs) were also investigated in normal and thalassemia patients. Human CD34+ progenitor cells were isolated from bone marrow and developed into EPs in the presence of EPO, SCF, and IL-3. Comparison among the normal individuals, patients with mild and severe thalassemia groups, revealed that erythropoiesis involves genes in a broad range of biological processes. The differentially expressed genes were associated with regulation of genes for the following functions: response to stress, anti-apoptosis, cell cycle, cell proliferation, and hematopoiesis. A large number of genes-related oxidative stresses were altered in thalassemia patients (e.g. MPO, SERPINH1, BIRC2, SNCA, and GPX1). Two of genes-regulated cell cycle was induced in mild diseases versus healthy volunteers (CUL4B and MSF) and some showed repression of genes-involved cell signaling (VEGF). Moreover, in severe thalassemias versus healthy subjects, some candidate genes such as CENPF and LIMS1 were augmented. Taken together, we noted that severe patients show slightly different of gene expression patterns from mild diseases. In conclusion, these findings addressed the expression of many genes, cooperation to regulate the erythroid proliferation, differentiation and apoptosis. These candidate genes expressed differentially among patients and controls.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/1487
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