scholarly journals Loss of alpha globin genes is associated with improved microvascular function in patients with sickle cell anemia

2021 ◽  
Vol 96 (5) ◽  
Author(s):  
Marc Romana ◽  
Karen Reminy ◽  
Berenike Moeckesch ◽  
Keyne Charlot ◽  
Marie‐Dominique Hardy‐Dessources ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Function ◽  
Globin Genes ◽  
Alpha Globin

Influence of Globin Gene Modifiers on Baseline and Hydroxyurea-Induced Fetal Hemoglobin Levels in Children with Sickle Cell Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3171-3171
Author(s):  
Russell E. Ware ◽  
Barry Eggleston ◽  
Tatiana Abramova ◽  
Sherri A. Zimmerman ◽  
Alice Lail ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Gamma Globin ◽  
Alpha Globin ◽  
Hydroxyurea Therapy

Abstract Fetal hemoglobin (HbF) is recognized as a major determinant of clinical disease severity in children and adults with sickle cell anemia (SCA). Patients with elevated HbF levels have a milder disease course, and many current therapeutic protocols for SCA include pharmacological induction of HbF. However, baseline and treatment HbF levels vary widely due to presumed genetic and environmental factors. Recognized globin gene modifiers of HbF include the beta globin haplotype and a potential contribution from concomitant alpha thalassemia. To characterize more fully the influence of globin gene modifiers on both baseline and treatment HbF levels, we retrospectively determined the beta globin haplotype (Benin, CAR, Senegal, Cameroon, or Arab-Indian) by selective gamma globin gene nucleotide sequencing and the alpha globin gene number (2, 3, or 4) by PCR for 67 African-American children with SCA receiving hydroxyurea therapy at stable maximal tolerated dose (MTD). The four beta globin haplotypes and frequencies identified in our cohort of children include Benin (0.61), CAR (0.17), Senegal (0.12), and Cameroon (0.10). The number of alpha globin genes and frequencies identified were 4 genes (0.72), 3 genes (0.25) and 2 genes (0.03). Baseline and MTD HbF levels were analyzed according to each variable. The average baseline HbF value for the entire cohort of children was 7.7 ± 4.4% (median 7.6%, range 1.3 – 19.3%), while the average treatment HbF value was 23.9 ± 7.2 % (median 22.9%, range 10.2 – 40.7%). All 67 children increased their HbF in response to hydroxyurea therapy (median 16.7%, range 5.0 – 28.8%). There was a modest but statistically significant correlation between the baseline and treatment HbF (r=0.66, p<.0001). The estimated effect of one unit change in baseline HbF on treatment HbF was 1.11 (95% CI of 0.78, 1.43). When baseline %HbF was analyzed according to the beta globin haplotype, the overall ANOVA had a p-value of 0.02, indicating a statistically significant influence. Further analysis confirmed associations previously identified in adults with SCA, i.e. children with at least one copy of the CAR haplotype had a lower baseline HbF (5.9% vs 8.4%, p=.05), while those with at least one copy of the Senegal haplotype had a higher baseline HbF (11.1% vs 6.7%, p<.001). When hydroxyurea MTD (treatment) HbF values were analyzed according to beta globin haplotype while adjusting for baseline HbF, however, the effect of beta globin haplotype was not statistically significant (p=.13). Analyses of HbF according to alpha globin gene number revealed no statistically significant effects on either baseline or treatment HbF values. Taken together, these data support the hypothesis that beta globin haplotype significant influences baseline HbF values for children with SCA, but has no significant effects on hydroxyurea MTD HbF values. Accordingly, children with SCA should be offered hydroxyurea based solely on clinical indications, without consideration of baseline HbF or beta globin haplotype. Even children with low baseline HbF values or the CAR beta globin haplotype can respond to hydroxyurea therapy with an elevated %HbF. Future studies designed to identify genetic modifiers of treatment HbF values should focus on sequence polymorphisms in non-globin genes that have trans-acting effects on gamma globin gene expression.

scholarly journals Rheologic predictors of the severity of the painful sickle cell crisis

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1216-1223 ◽  
Author(s):  
SK Ballas ◽  
J Larner ◽  
ED Smith ◽  
S Surrey ◽  
E Schwartz ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Vascular Endothelium ◽  
Hematological Parameters ◽  
Globin Gene ◽  
Globin Genes ◽  
Sickle Erythrocytes ◽  
Alpha Globin ◽  
Painful Crisis ◽  
Rbc Deformability

Abstract Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.

scholarly journals Rheologic predictors of the severity of the painful sickle cell crisis

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1216-1223
Author(s):  
SK Ballas ◽  
J Larner ◽  
ED Smith ◽  
S Surrey ◽  
E Schwartz ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Vascular Endothelium ◽  
Hematological Parameters ◽  
Globin Gene ◽  
Globin Genes ◽  
Sickle Erythrocytes ◽  
Alpha Globin ◽  
Painful Crisis ◽  
Rbc Deformability

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.

scholarly journals An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 1111-1117 ◽  
Author(s):  
YC Chang ◽  
KD Smith ◽  
RD Moore ◽  
GR Serjeant ◽  
GJ Dover
Keyword(s):  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Cohort Group ◽  
Five Factors ◽  
F Cells ◽  
Alpha Globin

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).

scholarly journals 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 370-380 ◽  
Author(s):  
TJ Ley ◽  
J DeSimone ◽  
CT Noguchi ◽  
PH Turner ◽  
AN Schechter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Peripheral Blood ◽  
Bone Marrow Cells ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Gamma Globin ◽  
Globin Synthesis ◽  
Marrow Cells

Abstract We previously demonstrated that 5-azacytidine can selectively increase gamma-globin synthesis in a patient with beta +-thalassemia, prompting us to treat two patients with sickle cell anemia and two additional patients with beta + thalassemia. 5-Azacytidine (2 mg/kg/day) was continuously infused for 7 days with no apparent clinical toxicity. The gamma/beta-globin biosynthetic ratio increased fourfold to sixfold in the bone marrow cells of each patient after treatment and remained elevated for 7–14 additional days. Hypomethylation of DNA near the gamma-globin genes in bone marrow cells was demonstrated 2 days after beginning the 5-azacytidine infusion. The peripheral blood fetal hemoglobin (HbF) level increased from 6.0% to 13.7% in one patient with sickle cell anemia and from 1.6% to 8.9% in the second. Stractan gradient analyses of peripheral blood from patients with sickle cell anemia revealed a marked decrease in the percentage of dense cells (cells that contain increased amounts of HbS polymer when deoxygenated) following treatment. These observations provide an impetus to investigate the effects of repeated courses of 5-azacytidine in a small group of severely ill patients to determine whether this drug may have a role in the treatment of patients with sickle cell anemia and beta- thalassemia.

scholarly journals Genetic Correction of Sickle Cell Anemia and β-Thalassemia: Progress and New Perspective

2010 ◽  
Vol 10 ◽  
pp. 644-654 ◽  
Author(s):  
Ajay Perumbeti ◽  
Punam Malik
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Genes ◽  
Induced Pluripotent Cells ◽  
Substantial Progress ◽  
Lentivirus Vectors ◽  
New Perspective ◽  
Induced Pluripotent ◽  
New Strategies

Gene therapy for β-globinopathies, particularly β-thalassemia and sickle cell anemia, holds promise for the future as a definitive corrective approach for these common and debilitating disorders. Correction of the β-globinopathies using lentivirus vectors carrying the β- or γ-globin genes and elements of the locus control region has now been well established in murine models, and an understanding of "what is required to cure these diseases" has been developed in the first decade of the 21st century. A clinical trial using one such vector has been initiated in France with intriguing results, while other trials are under development. Vector improvements to enhance the safety and efficiency of lentivirus vectors are being explored, while new strategies, including homologous recombination in induced pluripotent cells, for correction of sickle cell anemia have shown proof-of-conceptin vitro. Here, a review is provided of the current substantial progress in genetic correction of β-globin disorders.

scholarly journals Prevalence of Sickle Cell Anemic Subjects from Gadchiroli District, Maharashtra, India

2021 ◽  
Vol 9 (12) ◽  
pp. 1598-1602
Author(s):  
S. R. Kohchale
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sickle Cell Trait ◽  
Psychological Trauma ◽  
High Morbidity ◽  
Beta Globin ◽  
Cell Disease ◽  
Alpha Globin ◽  
Study District

Abstract: Sickle cell disease is caused by Mutations in the HBB gene. Hemoglobin consists of four protein subunits, typically, two subunits called alpha-globin and two subunits called beta-globin. People with sickle cell anemia suffers with high morbidity and with many intercurrent infections, people of study district are with high economic burden, terminate fatality in childhood state and have the emotional and psychological trauma including the family members the exact magnitude of the problem in the study district is still obscure. The study conducted from April 2009 to April 2012 to know the prevalence of sickle cell anemia by month long survey and by visiting all PHC’S and RH of district and data collected to know the prevalence of sickle cell trait and sickle cell disease total 7763 cases were recorded in present study and age wise, gender wise and caste wise distribution recorded and the data was analyzed statistically. Keywords: Sickle, anemia, Gadchiroli, Haemoglobin, beta-globin

scholarly journals Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1353-1360 ◽  
Author(s):  
MH Steinberg ◽  
W Rosenstock ◽  
MB Coleman ◽  
JG Adams ◽  
O Platica ◽  
...  
Keyword(s):  
Gene Mapping ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Hemoglobin Concentration ◽  
Reciprocal Relationship ◽  
Acute Chest Syndrome ◽  
Mean Corpuscular Hemoglobin ◽  
Aseptic Necrosis ◽  
Alpha Thalassemia ◽  
Alpha Globin

Abstract The characteristic clinical heterogeneity of sickle cell anemia (HbSS) may be, in part, a result of its interactions with alpha-thalassemia. Although alpha-thalassemia clearly affects some hematologic features of HbSS, its role in modulating the vasoocclusive severity of disease is not clear. To further explore this relationship, we examined the incidence of painful episodes, acute chest syndrome, aseptic bone necrosis, and leg ulcers in 3 patient groups with sickle cell disease: (1) 2,147 patients over age 2 yr, stratified according to mean corpuscular volume (MCV); (2) 183 patients selected on the basis of microcytosis and elevated HbA2, on whom globin biosynthesis studies were done; and (3) 125 patients who had alpha-globin genotype assigned by restriction endonuclease gene mapping. When patients were stratified by MCV, there was a reciprocal relationship between HbA2 levels and MCV, reflecting the presence of patients with beta o and alpha- thalassemia in the low MCV groups. The erythrocyte indices and HbA2 levels in patients classified as HbSS-alpha-thalassemia, by either globin synthesis studies or gene mapping, were very similar to those previously reported by others. Neither microcytosis, beta o, or alpha- thalassemia appeared to provide any clear protection from the vasoocclusive complication evaluated, and the prevalence of aseptic necrosis was increased in patients with microcytosis over age 20 yr and in groups with alpha-thalassemia. The effects of a reduced MCV and mean corpuscular hemoglobin concentration (MCHC), of possible benefit by themselves, when accompanied by a reduction in hemolysis and rise in hemoglobin concentration, as in HbSS-alpha-thalassemia, may cause sufficient rise in blood viscosity in critical vascular beds to impair blood flow and negate any amelioration of vasoocclusive complications in HbSS.

scholarly journals Alpha globin gene number: population and restriction endonuclease studies

Blood ◽  
1980 ◽  
Vol 55 (4) ◽  
pp. 706-708 ◽  
Author(s):  
G Brittenham ◽  
B Lozoff ◽  
JW Harris ◽  
YW Kan ◽  
AM Dozy ◽  
...  
Keyword(s):  
Restriction Endonuclease ◽  
Sickle Cell ◽  
Genetic Model ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Restriction Endonuclease Analysis ◽  
Globin Genes ◽  
Gene Number ◽  
Alpha Globin ◽  
Study Population

Abstract Restriction endonuclease analysis was used to test a proposed genetic model using alpha-globin gene number to account for the observed distributions of the proportions of hemoglobin (Hb) S in sickle cell trait. In a subsample of specimens collected during a population survey in India, these studies confirmed that the postulated genotype was present in 22 of the 23 individuals examined. In the study population, the number of alpha-globin genes explains about 90% of the variance in the proportion of HbS in sickle cell trait (r2 = 0.895, p less than 10(- 10)).

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