ArticleExperimental biology and medicine (Maywood, N.J.)2016
Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease.
Article in Experimental biology and medicine (Maywood, N.J.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 2 of them syntheses that pooled it.
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Who cites it
16 citing papers in PubMed, 2 syntheses or guidelines pooled it, 28 citations in OpenAlex.
- Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.International journal of molecular sciences · 2024Pooled it
- Genetic Variation and Sickle Cell Disease Severity: A Systematic Review and Meta-Analysis.JAMA network open · 2023Pooled it
- Spliceosome protein EFTUD2: A potential pathogenetic factor in tumorigenesis and some developmental defects (Review).Molecular medicine reports · 2025Review
- FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries.Nature communications · 2025Article
- A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds.HemaSphere · 2024Article
- Article
- Whole-genome resequencing of Sorghum bicolor and S. bicolor × S. halepense lines provides new insights for improving plant agroecological characteristics.Scientific reports · 2022Article
- Down-regulation of the transcriptional repressor ZNF802 (JAZF1) reactivates fetal hemoglobin in βScientific reports · 2022Article
- Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine.Scientific reports · 2021Article
- Unique Polymorphisms atJournal of personalized medicine · 2021Article
- The Genetic and Clinical Significance of Fetal Hemoglobin Expression in Sickle Cell Disease.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2021Review
- Association of polymorphisms in the HBG1-HBD intergenic region with HbF levels.Journal of clinical laboratory analysis · 2020Article
- Genetic variants in the G gamma-globin promoter modulate fetal hemoglobin expression in the Colombian population.Genetics and molecular biology · 2020Article
- Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies.Journal of clinical medicine · 2019Article
- Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease.Molecular diagnosis & therapy · 2019Review
- Sickle cell disease severity: an introduction.Experimental biology and medicine (Maywood, N.J.) · 2016Article
Corrections and comments
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Authors and funding
9 authors at 7 institutions in 1 country.
Funding
Abstract
Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the β-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' of δ-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 Gγ-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated γ-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production.
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Registered trials
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