scholarly journals Existence of HbF Enhancer Haplotypes atHBS1L-MYBIntergenic Region in Transfusion-Dependent Saudiβ-Thalassemia Patients

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Cyril Cyrus ◽  
Chittibabu Vatte ◽  
J. Francis Borgio ◽  
Abdullah Al-Rubaish ◽  
Shahanas Chathoth ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorders ◽  
Fetal Hemoglobin ◽  
Taqman Assay ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Level Elevation ◽  
Hbf Level

Background and Objectives.β-Thalassemia and sickle cell disease are genetic disorders characterized by reduced and abnormalβ-globin chain production, respectively. The elevation of fetal hemoglobin (HbF) can ameliorate the severity of these disorders. In sickle cell disease patients, the HbF level elevation is associated with three quantitative trait loci (QTLs),BCL11A,HBG2 promoter, andHBS1L-MYBintergenic region. This study elucidates the existence of the variants in these three QTLs to determine their association with HbF levels of transfusion-dependent Saudiβ-thalassemia patients.Materials and Methods. A total of 174 transfusion-dependentβ-thalassemia patients and 164 healthy controls from Eastern Province of Saudi Arabia were genotyped for fourteen single nucleotide polymorphisms (SNPs) from the three QTL regions using TaqMan assay on real-time PCR.Results. Genotype analysis revealed that six alleles ofHBS1L-MYBQTL (rs9376090Cp=0.0009, rs9399137Cp=0.008, rs4895441Gp=0.004, rs9389269Cp=0.008, rs9402686Ap=0.008, and rs9494142Cp=0.002) were predominantly associated withβ-thalassemia. In addition, haplotype analysis revealed that haplotypes ofHBS1L-MYB(GCCGCACp=0.022) andHBG2 (GTTp=0.009) were also predominantly associated withβ-thalassemia. Furthermore, theHBS1L-MYBregion also exhibited association with the high HbF cohort.Conclusion. The stimulation of HbF gene expression may provide alternative therapies for the amelioration of the disease severity ofβ-thalassemia.

ANTXR1 Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease

2018 ◽  
Vol 140 (1) ◽  
pp. 55-59 ◽  
Author(s):  
Zhara A. Al-Ali ◽  
Rana K. Fallatah ◽  
Esra A. Aljaffer ◽  
Eman R. Albukhari ◽  
Neriman Sadek Al-Ali ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Real Time Pcr ◽  
Genetic Variants ◽  
Fetal Hemoglobin ◽  
Genetic Mutations ◽  
Cell Disease ◽  
Hbf Level ◽  
Intronic Variants

Disease severity of sickle cell anemia is highly variable, and it is commonly accepted that fetal hemoglobin (HbF) levels play a major role as an ameliorating factor. Investigation of genetic variants have identified several genes to be the principal influencers of HbF regulation. Here, we further elucidated the association of rs4527238 and rs35685045 of ANTXR1 genes in the context of HbF level variance in sickle cell anemia patients of the Arab-Indian haplotype. Samples from 630 sickle cell anemia patients were analyzed for the mutations at 2 specific locations of the ANTXR1 gene by TaqMan®-based real-time PCR. The CC genotype (p = 0.018) of rs4527238 and the TT genotype (p = 0.048) of rs35685045 of ANTXR1 were found to be significantly associated with low HbF expression. The frequency of the CC genotype of rs4527238 was observed to be high in the low HbF patient group compared to the high HbF group (p = 0.009). Likewise, the frequency of the TT genotype of rs35685045 was also high among the low HbF group (p = 0.017). The ANTXR1 genetic mutations and the association with HbF expression in the Arab-Indian haplotype sickle cell patients revealed that the ANTXR1 gene may be a major HbF modulator leading to potential therapeutic options that should be further explored.

Early Predictors of Fetal Hemoglobin Response to Hydroxyurea in Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2344-2344
Author(s):  
Kristine Partovi ◽  
Sabrina Martyr ◽  
Vicki McGowan ◽  
Roberto Machado ◽  
James Taylor ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Maximal Response ◽  
Cell Disease ◽  
Mean Values ◽  
Total Hemoglobin ◽  
Early Predictors ◽  
Family Conference ◽  
Hbf Level

Abstract We investigated the kinetics of hematologic change in patients with sickle cell disease (SCD, HbSS, n=6) or SC disease (HbSC, n=1) who had been newly started on hydroxyurea (HU), with the intention of identifying early correlates to fetal hemoglobin (HbF) responsiveness. We found that HbF increased in all patients on HU, and that the half-maximal degree of HbF response could be estimated by 2 months, in patients’ whose MCVs had risen ≥ 10% above baseline. All 7 patients were treated with HU and followed closely for 6 months or more, until hematologic stability. Hematologic stability was apparent by ≥ 5 months. White blood cell count (WBC), absolute neutrophil count (ANC), reticulocyte (retic) count, % HbF, and mean corpuscular volume (MCV) were examined at bi-weekly intervals. Baseline values (1 or 2 values averaged) were compared with mean values obtained during weeks 2 to 8 (3 or 4 values averaged). As expected, by 2 months WBC and ANC had fallen 30 +/− 8% and 26 +/− 8%, respectively. Change in total hemoglobin (5.8 +/−6.7%), total platelet count (less 11 +/− 10.8%), and LDH (5.3 +/− 8.7%) was not consistent during this two month interval. By eight weeks after initiation of HU, retic counts had dropped in all six SS patients, from 15 to 52% less than baseline while MCV rose 9–21% above baseline; in general, rise in MCV preceded the rise in HbF. Overall, by the time of hematologic stability, all patients had increased their percent HbF, at between 3–8.5-fold relative to baseline; baseline percent HbF of total hemoglobin (Hgb) ranged from 0.7 to 8.3% and, after stabilization, from 5.2% to 24.9%. Maximal percentage of Hgb that was accounted for by HbF at stabilization was arbitrarily set at 100; at 8 weeks, all patients had achieved ≥ 42% of their maximal HbF level, mean 55 +/− 9.4% of maximum HbF. Two additional patients in whom extensive lab data were available, but who were suspected to be non-compliant or sub-therapeutically treated, had a >10% rise in MCV that was temporally associated with an inflection upward for HbF. Patient 8 had mean bi-weekly MCVs of 94, 91, 93, and, after a family conference, 102 (p=.003); Concurrent HbF was 7, 6, 6 and then 10 (p=.046). Patient 9 had mean bi-weekly MCVs on low-dose HU of 97, 96, and, after dose adjustment, 109(p=.003); HbF was 2%, 3%, and then 5 (p=.0094). We speculate that, in many patients, an increase in MCV above baseline of ≥ 10% is a marker of adequate HU dosing, and that HbF levels at that time approximate half-maximal response. A larger series will be necessary to confirm this relationship; a predictive model, correlating MCV and HbF responsiveness, could be used to determine sufficiency of, and compliance to, HU therapy, and to early identify patients who are at high-risk from SCD (e.g. with pulmonary hypertension) whose HbF responsiveness may not be adequate from HU alone. Figure Figure

scholarly journals Prevalence of pain-related single nucleotide polymorphisms in patients of African origin with sickle cell disease

2015 ◽  
Vol 16 (16) ◽  
pp. 1795-1806 ◽  
Author(s):  
Ellie H Jhun ◽  
Yingwei Yao ◽  
Ying He ◽  
A Kyle Mack ◽  
Diana J Wilkie ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Single Nucleotide Polymorphisms ◽  
Sickle Cell ◽  
Nucleotide Polymorphisms ◽  
African Origin ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Prevalence Of Pain

scholarly journals Single Nucleotide Polymorphisms in SAR1A Codon Regions Associated with Hydroxyurea Response in Sickle Cell Disease and Potentially Influenced in Mirnas Binding

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 987-987
Author(s):  
Chutima Kumkhaek ◽  
Christine Kim ◽  
James G. Taylor ◽  
Jianqiong Zhu ◽  
Wulin Aerbajinai ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Single Nucleotide Polymorphisms ◽  
Sickle Cell ◽  
Genetic Variants ◽  
Clinical Heterogeneity ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Hbf Induction

Therapeutic induction of fetal hemoglobin (HbF) is one of the most promising approaches to ameliorate the severity of hemoglobinopathies such as β-thalassemia and sickle cell disease (SCD). Among HbF induction agents, hydroxyurea (HU) was approved by FDA to use for the treatment of SCD. However, there is variability in HU response among SCD patients. Individual genetic variants are mostly influenced in differences in pharmacological responsiveness to drug. We previously reported that the small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR1A) protein was a specific HU-inducible gene. The single nucleotide polymorphisms (SNPs) in SAR1A promoter also contributed to inter-individual differences in regulation of HbF expression and SCD patient responses to HU. Additionally, microRNAs (miRNAs) have been identified as potential key genes that regulate HbF induction and related with the clinical heterogeneity of SCD. Here, we demonstrate that SNPs within SAR1A coding regions are associated with differences in individual responses to HU therapy and potentially influenced in miRNAs binding. In order to determine SNPs in SAR1A coding regions, we sequenced all 8 exons of SAR1A gene in 32 SCD patients. Three (rs56090714, rs3812693, rs56381518)and twenty-four (rs78341510, rs114346554, rs72807054, rs1370644731, rs1491135303, rs1412150420, rs1423653432, rs1480964347, rs1479076497, rs1180306451, rs1482823291, rs1275470720, rs201493587, rs1470556171, rs2394643, rs80028936, rs7919647, rs115340990, rs15801, rs1046747, rs79535872, rs7653, rs1280408553, and rs10586) variants were identified in codon 1 and 8, respectively. Interestingly, codon 2 was found a novel mutation at position 119, C>A. No mutation was detected in codon 3, 4, 5, 6 and 7. Among these SNPs, rs7919647 at codon 8 was highest frequency (96.9%) in SCD patients. Next, we analyzed the association of SNPs and clinical and laboratory profiles using multiple regression. The rs56381518, rs1479076497, rs1180306451, rs1482823291, rs2394643 and rs115340990 showed significant association with total Hb levels after HU treatment in SCD patients. Only rs1180306451 was associated with absolute HbF levels (P= 0.0161). While no SNPs were observed significant association with HbF, F-cell or F-reticulocyte levels. In addition, the potential miRNAs binding to SNPs at 3'UTR regions were determined by using MicroSNiPer. We found miRNAs that may bind to SNPs as shown in Table 1. miR-625-5p, miR-5003-3p, miR-1236-5p, miR4271, miR-345-3p, miR4725-3p, miR-378a-3p, miR-548q and miR-135a-3p were previously identified only in mild-SCD patients. Furthermore, it has been reported that miR-1200 and miR-19b-1-5p were differentially expressed in high HbF levels condition. Our findings highlight the importance of genetic variants in SAR1A codon region that may predict the hydroxyurea response in SCD patients and miRNAs role in clinical heterogeneity of SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Glucocorticoid receptor single nucleotide polymorphisms are associated with acute crisis pain in sickle cell disease

2018 ◽  
Vol 19 (13) ◽  
pp. 1003-1011 ◽  
Author(s):  
Ellie H Jhun ◽  
Nilanjana Sadhu ◽  
Yingwei Yao ◽  
Ying He ◽  
Robert E Molokie ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Single Nucleotide Polymorphisms ◽  
Glucocorticoid Receptor ◽  
Sickle Cell ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Acute Crisis

scholarly journals A cautionary note regarding hydroxyurea in sickle cell disease

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1124-1128
Author(s):  
EP Vichinsky ◽  
BH Lubin
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Course ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
History Of ◽  
Hbf Level

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

scholarly journals High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte.

2020 ◽  
Author(s):  
Narcisse Elenga ◽  
Abdourahim CHAMOUINE ◽  
Thoueiba SAANDI ◽  
Mathias MUSZLAK ◽  
Juliette LARMARAUD ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Significant Risk ◽  
Fetal Hemoglobin ◽  
Biological Data ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Increased Risk ◽  
Remarkable Result ◽  
Lost To Follow Up

Abstract Background: Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia, specific to each population, would be prognostically useful and could inform personalized therapeutics. The objective of this study was to describe the genetic modulators of sickle cell disease in a cohort of pediatric patients followed up in Mayotte. Methods: In this retrospective cohort study, clinical and biological data, collected between 1 January 2007 and 31 December 2017, in children younger than 18 years, were considered for the analysis. Results: We included 185 children with 72 % SS, 16 % Sβ0-thalassemia and 12 % Sβ+ thalassemia. The mean age was 9.5 years; 10 % of patients were lost to follow up. The Bantu haplotype was associated with an increase in hospitalizations and transfusions. The alpha-thalassemic mutation was associated with a decrease of hemolysis biological parameters (anemia, reticulocytes), and less cerebral vasculopathy. The Single Nucleotide Polymorphisms BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were associated with the group of children with HbF> 10%. The survival analysis without occurrence of cerebral vasculopathy showed that the group of patients with HbF> 10% presented a significant risk of early onset of cerebral vasculopathy. Conclusions: The most remarkable result of our study was the association of SNPs with the phenotypic groups that we aimed to determine. BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were correlated with the HbF group> 10%, which presents a higher risk of cerebral vasculopathy and would be oriented towards the hemolytic sub-phenotype.

scholarly journals Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease

2021 ◽  
Vol 11 (6) ◽  
pp. 567
Author(s):  
Nagihan Akbulut-Jeradi ◽  
Maria Jinky Fernandez ◽  
Rasha Al Khaldi ◽  
Jalaja Sukumaran ◽  
Adekunle Adekile
Keyword(s):  
Quantitative Trait Loci ◽  
Sickle Cell Disease ◽  
Single Nucleotide Polymorphisms ◽  
Sickle Cell ◽  
Quantitative Trait ◽  
Sanger Sequencing ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Unique Snps

Patients with sickle cell disease (SCD) in Kuwait have elevated HbF levels ranging from ~10–44%; however, the modulating factors are unclear. We investigated the association of single nucleotide polymorphisms (SNPs) at BCL11A, HBS1L-MYB and HBB with HbF levels in 237 Kuwaiti SCD patients, divided into 3 subgroups according to their HbF levels. Illumina Ampliseq custom DNA panel was used for genotyping and confirmed by arrayed primer extension or Sanger sequencing. In the BCL11A locus, the CC genotype of rs7606173 [χ2 = 16.5] and (GG) of rs10195871 [χ2 = 15.0] were associated with Hb-F1 and HbF-2 subgroups, unlike rs1427404-T [χ2 = 17.3], which showed the highest association across the three subgroups. HBS1L-MYB locus revealed 2 previously-described SNPs (rs66650371 [χ2 = 9.5] and rs35795442 [χ2 = 9.2]) and 2 previously-unreported SNPs, (rs13220662 [χ2 = 6.2] and rs1406811 [χ2 = 6.7]) that were associated with the HbF-3 subgroup, making this the key locus elevating HbF to the highest levels. HBB cluster variants were associated with lower levels of HbF (β = −1.1). We report four previously-unpublished variants showing significant association with HbF. Each of the three quantitative trait loci affects HbF levels differently; unique SNPs, especially in HBS1L-MYB, elevate HbF to the highest levels.

Sickled Erythrocyte Morphology in the Bone Marrow of Patients with Sickle Cell Disease: Previously Unrecognized Forms of Sickled Erythrocytes May Have a Pathogenetic Role in Bone Pain of Painful Crises.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3802-3802
Author(s):  
George T. Roberts
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Peripheral Blood ◽  
Morphological Characteristics ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Erythrocyte Morphology ◽  
Pathogenetic Role ◽  
Hbf Level

Abstract Background: The painful crises of sickle cell disease (SCD) are characteristically localized to the skeleton. Various lines of evidence suggest that bone and bone marrow (BM) infarction contribute to the pathophysiology of such pain in which sickled red blood cells (SRBC) are believed to play a part. However, there is little information about the morphological characteristics and role of SRBC in BM during the crises or indeed, in the “steady state”. Occasional light microscopic observations in the BM of SCD patients show numerous markedly distorted cells, presumed to be SRBC, types of which have not been previously reported from this site or the peripheral blood (PB). We therefore studied a series of BM biopsies from SCD patients to determine whether such changes are consistently present. Methods: We microscopically reviewed archival BM biopsies from SCD patients for abnormally shaped RBC and compared the findings with SRBC on Wright-stained smears of PB collected simultaneously with the biopsies. The material consisted of Wright-Giemsa stained smears of aspirated BM and hematoxylin-eosin stained histological sections of clotted aspirate and / or trephine biopsies. We also examined fresh BM RBC by scanning and transmission electron microscopy (EM). We determined the relationship between the percentage of SRBC in BM and PB on the one hand, and fetal hemoglobin (HbF) levels on the other. Results: We studied the BM of 43 SCD patients. By LM, we observed markedly distorted RBC in the BM of the majority of patients who also had BM SRBC that were more typical forms. The distorted forms included vastly elongated erythrocytes, measuring up to 40 microns in length and less than 1 micron in width, some fixed into rod like structures, but others as sinuous, snake-like forms that have not been previously described. Scanning EM appearances also confirmed the features observed by LM. By contrast, none of PB samples showed similarly distorted SRBC. Although the percentage of typical SRBC in BM was concordant with that in the PB (p<0.001) SRBC numbers in both PB and BM were inversely proportional to the level of HbF.(Table 1) Conclusion: We conclude that the proportions of markedly distorted SRBC present in the BM of SCD patients are inversely proportional to HbF level and may thus play a pathogenetic role in the localization of severe pain to the skeleton during painful crises. Table 1. Correlations between sickled RBC estimates and blood fetal hemoglobin levels MSRBC MARROW MBMSRBC MSRBCLOT+TREPHINE MSRBC PB MSRBC= Mean SRBC marrow and peripheral blood together. MBMSRBC = Mean SRBC in bone marrow aspirates only. MSRBCLOT+TREPHINE = Mean SRBC, clotted marrow aspirate and trephine together. MSRBCPB = Mean SRBC in peripheral blood. MHbF = Mean HbF level in blood. r = correlation coefficient. NS = Not significant. MHbF MHbF MHbF MHbF r −0.3806 −0.3293 −0.2685 −0.384 p < 0.05 < 0.05 NS < 0.05

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