Association between Variants at <i>BCL11A</i> Erythroid-Specific Enhancer and Fetal Hemoglobin Levels among Sickle Cell Disease Patients in Cameroon: Implications for Future Therapeutic Interventions

Pule, Gift D.; Bitoungui, Valentina Josiane Ngo; Chemegni, Bernard Chetcha; Kengne, André Pascal; Antonarakis, Stylianos E.; Wonkam, Ambroise

doi:10.1089/omi.2015.0124

Cited by 19 publications

(18 citation statements)

References 25 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…60,61 Therefore, the erythroid enhancer is an attractive DNA element for lineage-specific BCL11A gene silencing as a strategy for gene therapy in SCD and b-thalassemia.…”

mentioning

confidence: 99%

Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease

Liu¹,

Pertsemlidis

Ding

et al. 2016

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the b-globin (HBB) gene on chromosome 11. However, people with the same genetic mutation display a wide range of clinical phenotypes. Fetal hemoglobin (HbF) expression is an important genetic modifier of SCD complications leading to milder symptoms and improved long-term survival. Therefore, we performed a genome-wide association study (GWAS) using a case-control experimental design in 244 African Americans with SCD to discover genetic factors associated with HbF expression. The case group consisted of subjects with HbF!8.6% (133 samples) and control group subjects with HbF 3.1% (111 samples). Our GWAS results replicated SNPs previously identified in an erythroid-specific enhancer region located in the second intron of the BCL11A gene associated with HbF expression. In addition, we identified SNPs in the SPARC, GJC1, EFTUD2 and JAZF1 genes as novel candidates associated with HbF levels. To gain insights into mechanisms of globin gene regulation in the HBB locus, linkage disequilibrium (LD) and haplotype analyses were conducted. We observed strong LD in the low HbF group in contrast to a loss of LD and greater number of haplotypes in the high HbF group. A search of known HBB locus regulatory elements identified SNPs 5 0 of d-globin located in an HbF silencing region. In particular, SNP rs4910736 created a binding site for a known transcription repressor GFi1 which is a candidate protein for further investigation. Another HbF-associated SNP, rs2855122 in the cAMP response element upstream of Gg-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated g-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production.

show abstract

“…60,61 Therefore, the erythroid enhancer is an attractive DNA element for lineage-specific BCL11A gene silencing as a strategy for gene therapy in SCD and b-thalassemia.…”

mentioning

confidence: 99%

Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease

Liu¹,

Pertsemlidis

Ding

et al. 2016

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

show abstract

“…22,23 These may account for up to 30% of the variability, and the significance of these loci seems to be population dependent. 24,25 Other modulators of response to hydroxycarbamide include renal profiles, body mass index and marrow reserve. 26 Previous studies that have operated under the MTD have primarily been based in the United States.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of hydroxycarbamide in children with sickle cell disease – Analysis of dose‐response metrics in a large birth cohort in a tertiary sickle cell centre

Park

Bhatti

Chakravorty

2019

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Background Despite the well‐established efficacy of hydroxycarbamide in the management of sickle cell disease (SCD), the paucity of real‐world clinical data limits the establishment of a practical dosing strategy. The aim of this study was to analyse the dose‐response metrics of hydroxycarbamide associated with the minimum effective dose protocol – specifically, between dose groups and differing degrees of myelosuppression. Design/methods A retrospective cohort study was conducted on 93 patients who were initiated on hydroxycarbamide between 2005 and 2017 at a tertiary haemoglobinopathy centre in London, UK. The burden of acute SCD‐related complications was defined by the annualised rates of emergency department attendances and hospital admissions. Secondary outcomes included haematological, biochemical, liver, renal and transcranial Doppler velocity status. Comparisons were performed upon stratification via dose (<20 mg/kg/day, 20–24 mg/kg/day and ≥25 mg/kg/day) and sustained absolute neutrophil count (ANC) values (ANC <4 × 109/L and ANC ≥4 × 109/L). Results Clinical outcomes were not predicted by dose or ANC values. Whilst laboratory indices between dose groups were also non‐statistically significant, patients maintained on ANC <4 × 109/L were shown to achieve superior responses in haemoglobin, haemoglobin F, absolute reticulocyte count and liver function. Toxicities occurred idiosyncratically, with minimal reports of transient neutropaenia and thrombocytopaenia. Conclusions Objective clinical responses may be achievable without intensive dose escalation. Our finding that greater myelosuppression is associated with greater improvements in laboratory markers of clinical benefit is consistent with prior clinical trials, but ongoing effectiveness studies are needed to determine whether these benefits can be reliably demonstrated in routine clinical practice using different dosing protocols.

show abstract

“…[8][9][10] Other variants in the BCL11A erythroid-specific enhancer (rs1427407 and rs7606173) have been shown to account for 8% and 6.2% of HbF variance, respectively, among SCD patient cohorts in the USA, [11,12] Tanzania [13] and Cameroon. [14] The co-inheritance of α-thalassaemia has also been associated with improved clinical manifestations of SCD. [15][16][17][18] Although the multiple independent origins of the HbS mutation have been questioned recently, [19] the SCD mutation is classically associated with five region-defined β-globin gene haplotypes, Benin, Bantu or Central African (CAR), Cameroon, Senegal and Indian-Arab, [20][21][22][23] four of which are from Africa and associated with malaria incidence.…”

Section: Researchmentioning

confidence: 99%

Burden, genotype and phenotype profiles of adult patients with sickle cell disease in Cape Town, South Africa

et al. 2017

View full text Add to dashboard Cite

Background. An exponential increase in the number of sickle cell disease (SCD) patients in paediatric services in Cape Town, South Africa, has been reported. The trend in adult/adolescent services has not been investigated. Objectives. To evaluate epidemiological trends of SCD and the profile of patients affected by SCD attending the Haematology Clinic at Groote Schuur Hospital (GSH), Cape Town. Methods. (i)A retrospective review of the number of SCD patients over the past 20 years; (ii) a cross-sectional analysis of clinical and haematological characteristics of SCD patients; and (iii) molecular analysis of the haemoglobin S mutation, the haplotype in the β-globinlike genes cluster, the 3.7 kb α-thalassaemia gene deletion and 19 selected single-nucleotide polymorphisms (SNPs) associated with fetal haemoglobin (HbF) levels. Results. From 1995 to 2016, 81 adolescent/adult patients with SCD were registered, mostly originating from other African countries (n=61, 75.3%). There was an increase of over 200% in new cases (n=47) during the last quarter of the two decades investigated. Data from 34 of 58 regular attendees (58.6%) were analysed. The mean age of the patients was 26.1 years (standard deviation (SD) 9.8), and 70.6% were male. With the exception of four patients with sickle/β-thalassaemia, all the patients had SCD (haemoglobin SS). The co-inheritance of a single 3.7 kb α-globin deletion was found in 42.3% of cases (n=11). The Bantu haplotype was the most observed (65.4% of chromosomes). Most HbF-promoting SNPs were not associated with variable levels of haematological indices. Conclusions.There is an increasing burden of adult SCD patients at GSH. National health and academic institutions need to adapt policies and healthcare professional training accordingly. S Afr Med RESEARCH Methods Ethical approvalThe study was performed in accordance with the Declaration of Helsinki and with the approval of the Faculty of Health Sciences Human Research Ethics Committee, University of Cape Town (HREC ref. no. 132/2010). Informed and written consent was obtained from adult participants (≥18 years), and for one patient aged 15 years informed consent was obtained from the guardian with assent from the participant. PatientsThe Haematology Clinic runs weekly every Wednesday. Most patients are seen at least once a month, and clinically stable patients every 3 months, with the exception of crisis-related hospitalisation.A retrospective review of the number of SCD patients attending the clinic over the past 20 years and a cross-sectional analysis of patients who regularly attend the clinic were performed. Clinical events and haematological indices were retrospectively collected from hospital records. The haematological measures were those reported at the first visit to the hospital. Molecular methods DNA extractionDNA was isolated from the peripheral blood using the AllPrep DNA/RNA/miRNA universal kit (Qiagen, USA) according to the manufacturer's instructions. GenotypingHbS mutation and β-globin haplotypes Polymerase chain reac...

show abstract

Association between Variants at BCL11A Erythroid-Specific Enhancer and Fetal Hemoglobin Levels among Sickle Cell Disease Patients in Cameroon: Implications for Future Therapeutic Interventions

Cited by 19 publications

References 25 publications

Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease

Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease

Effectiveness of hydroxycarbamide in children with sickle cell disease – Analysis of dose‐response metrics in a large birth cohort in a tertiary sickle cell centre

Burden, genotype and phenotype profiles of adult patients with sickle cell disease in Cape Town, South Africa

Contact Info

Product

Resources

About