BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia

Sebastiani, Paola; Farrell, John; Alsultan, A.; Wang, S.; Edward, Heather L.; Shappell, Heather; Bae, Harold; Milton, Jacqueline N.; Baldwin, Clinton T.; Al-Rubaish, Abdullah M.; Naserullah, Zaki A.; Al-Muhanna, Fahad; Alsuliman, Ahmed; Patra, P.K.; Farrer, Lindsay A.; Ngo, Duyen A.; Vathipadiekal, Vinod; Chui, David H.K.; Al-Ali, Amein K.; Steinberg, Martin H.

doi:10.1016/j.bcmd.2015.01.001

Cited by 36 publications

(35 citation statements)

References 31 publications

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“…The results are consistent with those reported among African Americans (Bauer et al, 2013) and patients from Saudi Arabia and India (Sebastiani et al, 2015) and Tanzania for rs1427407 (Ntatiro et al, 2015). The results of this study are of particular importance for the local and global FIG.…”

Section: Discussionsupporting

confidence: 83%

“…Two SNPs of the enhancer element had a stronger association with HbF levels among African American SCD patients: rs1427407 in DHS +62 and rs7606173 in DHS +55. This is consistent with the hypothesis that multiple functional SNPs act in combination to influence BCL11A regulation (Bauer et al 2013;Sebastiani et al, 2015).…”

Section: Introductionsupporting

confidence: 80%

“…Lastly, Sebastiani et al (2015) have reported on the association between variants at BCL11A erythroid-specific enhancer and HbF levels in African American SCD patients. However, among self-identified African Americans, analysis of genomic admixture indicates that the median proportion of European ancestry is 18.5% with very large variation, ranging from an estimate of over 99% West African ancestry less than 1% (Bryc et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Bioinformatics analysis suggests that rs7606173 in DHS +55 changes a binding site for MZF1, a gene actively transcribed in hematopoietic cells (Sebastiani et al, 2015) and most importantly, functional analysis have shown that the disruption of this enhancer would impair BCL11A expression in erythroid precursors and thus HbF expression, while conserving the ''undruggable'' nature of this transcription factor in non-erythroid lineages (Bauer et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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

Pule

Bitoungui

Chemegni

et al. 2015

OMICS: A Journal of Integrative Biology

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Variants in BCL11A were previously associated with fetal hemoglobin (HbF) levels among Cameroonian sickle cell disease (SCD) patients, however explaining only *2% of the variance. In the same patients, we have investigated the relationship between HbF and two SNPs in a BCL11A erythroid-specific enhancer (N = 626). Minor allele frequencies in rs7606173 and rs1427407 were 0.42 and 0.24, respectively. Both variants were significantly associated with HbF levels ( p = 3.11e-08 and p = 6.04e-06, respectively) and explained 8% and 6.2% variations, respectively. These data have confirmed a stronger effect on HbF of genomic variations at the BCL11A erythroid-specific enhancer among patients with SCD in Cameroon, the first report on a West African population. The relevance of these findings is of prime importance because the disruption of this enhancer would alter BCL11A expression in erythroid precursors and thus HbF expression, while sparing the induced functional challenges of any alterations on the expression of this transcription factor in non-erythroid lineages, thus providing an attractive approach for new treatment strategies of SCD.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Pule

Bitoungui

Chemegni

et al. 2015

OMICS: A Journal of Integrative Biology

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“…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)

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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.

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia

Cited by 36 publications

References 31 publications

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

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

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

Genetic Variation and Sickle Cell Disease Severity

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