scholarly journals Identical nucleotide sequences of the 3'A gamma globin gene enhancer elements from four different chromosomes

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 845-848 ◽  
Author(s):  
IS Han ◽  
HJ Huang ◽  
YT Zeng ◽  
KD Lanclos ◽  
TH Huisman
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Enhancer Element ◽  
Gamma Globin ◽  
Sickle Cell Anemia Patient ◽  
Gene Enhancer ◽  
Identical Nucleotide ◽  
Anemia Patient

Abstract We have determined the nucleotide sequence of the 2,360-bp long EcoRI fragment from four chromosomes; this fragment is located 3′ to the A gamma globin gene and is considered to contain the enhancer element identified by Bodine and Ley. The chromosomes were from an Arabian sickle cell anemia patient with high Hb F and a homozygosity for haplotype No 31 and from a black sickle cell anemia patient with low Hb F and a homozygosity for haplotype No 19. A third chromosome carried the determinant for a nondeletional hereditary persistence of fetal hemoglobin seen in a Chinese subject, and the fourth was a normal chromosome from a Yugoslavian subject. Twenty-one differences were observed when a comparison was made with the published sequence; no differences were seen between the sequences of the four different samples except for an additional mutation in the Chinese. These data make it unlikely that specific mutations within this sequence are associated with increases in G gamma and A gamma production.

scholarly journals Identical nucleotide sequences of the 3'A gamma globin gene enhancer elements from four different chromosomes

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 845-848
Author(s):  
IS Han ◽  
HJ Huang ◽  
YT Zeng ◽  
KD Lanclos ◽  
TH Huisman
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Enhancer Element ◽  
Gamma Globin ◽  
Sickle Cell Anemia Patient ◽  
Gene Enhancer ◽  
Identical Nucleotide ◽  
Anemia Patient

We have determined the nucleotide sequence of the 2,360-bp long EcoRI fragment from four chromosomes; this fragment is located 3′ to the A gamma globin gene and is considered to contain the enhancer element identified by Bodine and Ley. The chromosomes were from an Arabian sickle cell anemia patient with high Hb F and a homozygosity for haplotype No 31 and from a black sickle cell anemia patient with low Hb F and a homozygosity for haplotype No 19. A third chromosome carried the determinant for a nondeletional hereditary persistence of fetal hemoglobin seen in a Chinese subject, and the fourth was a normal chromosome from a Yugoslavian subject. Twenty-one differences were observed when a comparison was made with the published sequence; no differences were seen between the sequences of the four different samples except for an additional mutation in the Chinese. These data make it unlikely that specific mutations within this sequence are associated with increases in G gamma and A gamma production.

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 Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the beta-globin gene. Multicenter Study of Hydroxyurea

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1604-1611 ◽  
Author(s):  
ZH Lu ◽  
MH Steinberg
Keyword(s):  
Gene Expression ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Regulatory Sequences ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Globin Gene Expression

Very different fetal hemoglobin levels among adult sickle cell anemia patients suggest genetic modulation of gamma-globin gene expression. In sickle cell anemia, different fetal hemoglobin levels are associated with distinct beta-globin gene haplotypes. Haplotype may be a marker for linked DNA that modulates gamma-globin gene expression. From 295 individuals with sickle cell anemia, we chose for detailed studies 53 patients who had the highest or the lowest fetal hemoglobin levels and 7 patients whose fetal hemoglobin levels were atypical of their haplotype. In these individuals, we examined portions of the beta- globin gene locus control region hypersensitive sites two and three, an (AT)x(T)y repeat 5′ to the beta-globin gene, a 4-bp deletion 5 to the A gamma T gene, promoters of both gamma-globin genes, 5′ flanking region of the G gamma-globin gene, and A gamma-globin gene IVS-II. Of the regions we studied all polymorphisms were always haplotype-linked and no additional mutations were present. This suggested that variations in these areas are uncommon mechanisms of fetal hemoglobin modulation in sickle cell anemia. Whereas unexamined cis-acting sequences may regulate gamma-globin gene transcription, trans-acting factors may play a more important role.

scholarly journals Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 716-720 ◽  
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
N Olivieri ◽  
G Antognetti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
Hemoglobin F ◽  
Gamma Globin ◽  
Hemoglobin Production

Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5′ to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.

scholarly journals Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 716-720 ◽  
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
N Olivieri ◽  
G Antognetti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
Hemoglobin F ◽  
Gamma Globin ◽  
Hemoglobin Production

Abstract Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5′ to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.

Polyostotic osteomyelitis in a sickle cell anemia patient

2017 ◽  
Vol 8 (1) ◽  
pp. 54
Author(s):  
JohnAyodele Olaniyi ◽  
AkinyinkaOluwafemi Akinwunmi
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sickle Cell Anemia Patient ◽  
Anemia Patient

Genetic Polymorphisms Associated with Fetal Hemoglobin Response to Hydroxyurea in Patients with Sickle Cell Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 108-108 ◽  
Author(s):  
Diego F. Wyszynski ◽  
Clinton T. Baldwin ◽  
Mario Cleves ◽  
John J. Farrell ◽  
Alice Bisbee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Candidate Genes ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Linear Regression Analysis ◽  
Fetal Hemoglobin ◽  
Computer Application ◽  
Average Increase ◽  
Genetic Traits

Abstract Hydroxyurea (HU) is an effective treatment for most patients with symptomatic sickle cell anemia, yet the fetal hemoglobin (HbF) response to treatment is variable. A capacity to predict an individual’s HbF response to HU would aid the selection of patients for treatment and reduce toxicity from unfruitful dose escalation. Unfortunately, this is presently not possible. We hypothesized that HbF levels and the HbF response to HU are regulated as complex genetic traits and previously showed that 12 single nucleotide polymorphisms (SNPs), associated with a 20% to 30% difference in baseline HbF concentrations, were found in the introns of 4 genes, PDE7B, MAP7, MAP3K5 and PEX7, spanning the genomic region from 136.1 Mb to 137.5 Mb on chromosome 6q (Cell Mol Biol 50:23, 2004). To begin to define the genetic predictors of the HbF response to (HU), we examined SNPs in candidate genes and genetic loci in 214 patients with sickle cell anemia whose HbF levels were available before HU treatment was started and after these patients reached a stable dose of this drug. Forty-six candidate genes were chosen because of their possible role in HbF regulation and HU metabolism and 226 SNPs in these genes were examined by mass spectrometry. A computer application developed in STATA was used to carry out multiple linear regression analysis with simultaneous adjustment for age, sex and the α- and β-globin gene cluster haplotypes for each SNP and combinations of nearby SNPs. Dominant, codominant and recessive models for modulating HbF expression were tested. In this QTL analysis, SNPs in a member of the cytochrome P450 family (CYP2C9), in aquaporin 9 (AQP9) and in the chromosome 6q qtl described above were significantly associated with the HbF response to HU. The effect of genotype on the magnitude of HbF response to HU was examined for selected SNPs in AQP9 and CYP2C9. In AQP9, AA was associated with an average increase of 6% in HbF compared with GG (rs1867380; OR 6.6, p<0.001). In CYP2C9, AG was associated with an average increase of 3% and GG with an average increase of 11% (rs2209331; OR 1.6 and 7.5, p=0.05, 0.000). An effect was also noted for the 6q qtl. We also treated the increase in HbF as a discretized variable, comparing individuals in the lower two quartiles of HbF response with individuals in the top quartile of HbF response to HU (Blood 89:1078, 1997). These same genotypes were more common in good HU responders than in poor responders (p<0.05). CYP2C9 (10q24) encodes a member of the cytochrome P450 superfamily of enzymes, monooxygenases catalyzing many reactions involved in drug metabolism, plays some role in the metabolism of HU derivatives. AQP9 (15q22.1–22.1), belongs to a family of water-selective membrane channels and stimulates urea transport, permitting passage of many uncharged solutes. These results begin to define the pattern of genetic heterogeneity that may be used ultimately to predict a patient’s HbF response to HU. As multiple genes are very likely to play roles in this response, the interactions and predictive value of their polymorphisms will need to be modeled with methods that account for simultaneous associations.

scholarly journals Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

2020 ◽  
Vol 9 (11) ◽  
pp. 3782
Author(s):  
Martin H. Steinberg
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Point Mutations ◽  
Fetal Hemoglobin ◽  
Gene Deletions ◽  
Total Hemoglobin ◽  
Sickle Erythrocytes ◽  
Hereditary Persistence ◽  
Very High

Fetal hemoglobin (HbF) usually consists of 4 to 10% of total hemoglobin in adults of African descent with sickle cell anemia. Rarely, their HbF levels reach more than 30%. High HbF levels are sometimes a result of β-globin gene deletions or point mutations in the promoters of the HbF genes. Collectively, the phenotype caused by these mutations is called hereditary persistence of fetal hemoglobin, or HPFH. The pancellularity of HbF associated with these mutations inhibits sickle hemoglobin polymerization in most sickle erythrocytes so that these patients usually have inconsequential hemolysis and few, if any, vasoocclusive complications. Unusually high HbF can also be associated with variants of the major repressors of the HbF genes, BCL11A and MYB. Perhaps most often, we lack an explanation for very high HbF levels in sickle cell anemia.

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