What I’ve been reading . . .

• Genetic association studies finding variants in the BCL11A gene associated with increased fetal hemoglobin production
  • Uda et al., Genome-Wide Association Study Shows BCL11A Associated with Persistent Fetal Hemoglobin and Amelioration of the Phenotype of β-Thalassemia. Proceedings of the National Academy of Sciences 2008, 105 (5), 1620–1625. https://doi.org/10.1073/pnas.0711566105.
• Experiments showing BCL11A regulates HbF production in red blood cells
  • Sankaran et al., Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A. Science 2008, 322 (5909), 1839–1842. https://doi.org/10.1126/science.1165409.
• Structural biology study showing how BCL11A binds to the fetal hemoglobin promoter
  • Yang et al., Structural Insights into the Recognition of γ-Globin Gene Promoter by BCL11A. Cell Res 2019, 29 (11), 960–963. https://doi.org/10.1038/s41422-019-0221-0.
  • And check out the associated crystal structure in the PDB, ID 6ki6
• Paper showing some of the associations are in an erythroid specific enhancer
  • Bauer et al., Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level. Science 2013, 342 (6155), 253–257. https://doi.org/10.1126/science.1242088.
    • As nicely reviewed/highlighted in:
      • Hardison and Blobel. GWAS to Therapy by Genome Edits? Science 2013, 342 (6155), 206–207. https://doi.org/10.1126/science.1245813.
• And that disrupting that enhancer with CRISPR/Cas could increase HbF levels in red blood cells
  • Canver et al., BCL11A Enhancer Dissection by Cas9-Mediated in Situ Saturating Mutagenesis. Nature 2015, 527 (7577), 192–197. https://doi.org/10.1038/nature15521.
• Casgevy paper (first gene editing therapy for sickle cell disease and β-thalassemia, aka exagamglogene autotemcel (exa-cel))
  • Frangoul et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. New England Journal of Medicine 2021, 384 (3), 252–260. https://doi.org/10.1056/NEJMoa2031054.
• Paper reporting results of clinical trial using base editing to treat sickle cell disease (the therapeutic is called Ristoglogene autogetemcel (risto-cel), formerly known as BEAM-101)
  • Gupta et al., Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease. N Engl J Med 2026, 394 (18), 1824–1835. https://doi.org/10.1056/NEJMoa2504835.
• Review article on the γ-globin to β-globin switch:
  • Orkin, S. H. The Fetal-to-Adult Hemoglobin Switch — Mechanism and Therapy. N Engl J Med 2025, 392 (21), 2135–2149. https://doi.org/10.1056/NEJMra2405260.
• Review articles on gene editing and gene therapy techniques for sickle cell disease and related disorders
  • Tardif, M.; Saby, M.; Forté, S.; Pincez, T. The Journey of Gene Therapy in Sickle Cell Disease: How Molecular Advances Meet Clinical Care. Cells 2026, 15 (10), 939. https://doi.org/10.3390/cells15100939.
  • Levesque, S.; Bauer, D. E. CRISPR-Based Therapeutic Genome Editing for Inherited Blood Disorders. Nat Rev Drug Discov 2025, 24 (12), 907–925. https://doi.org/10.1038/s41573-025-01236-y.

And if you’re looking for some help with GWAS interpretation, etc.,:

• Manhattan Plots in GWAS: A Visual Guide”  https://metricgate.com/blogs/gwas-manhattan-plots-explained/ 
• Uffelmann et al., Genome-Wide Association Studies. Nat Rev Methods Primers 2021, 1 (1), 59. https://doi.org/10.1038/s43586-021-00056-9.
  • It’s paywalled at Nature, but there’s a free version here: https://research.vu.nl/ws/portalfiles/portal/155815846/Genome_wide_association_studies.pdf 

Some highlights – click figures to enlarge

And for a bit of context and background . . .

Some figures