bims-sicedi Biomed News
on Sickle cell disease
Issue of 2026–03–01
seventeen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Editorial: Unraveling inflammatory pathways in sickle cell disease: molecular, cellular and translational insights.
  2. Haploidentical transplantation in sickle cell disease: toward donor availability for all patients.
  3. Inflammatory markers in sickle cell disease during vaso-occlusive crisis.
  4. One cell at a time: HbF distribution in sickle cell disease.
  5. Comprehensive analysis of complement activation in a hydroxyurea-treated patient cohort with sickle cell disease.
  6. Genetic Contribution to Asthma Informs Acute Chest Syndrome Pathophysiology and Risk Stratification.
  7. Impact of HBS1L-MYB Gene Single Nucleotide Polymorphisms on Fetal Hemoglobin Expression in Moroccan Sickle Cell Anemia Children: Preliminary Results.
  8. Rethinking Sickle Cell Disease as a Systemic Vasculopathy.
  9. Three-year safety, efficacy, and renal outcomes of mitapivat treatment in sickle cell disease: results from the phase 2 open-label study.
  10. Sickle Cell Disease in Central India: Haematological and Clinical Insights from a Large Cohort of Patients.
  11. Diagnosis and Management of Acute Chest Syndrome in Children With Sickle Cell Disease.
  12. Haematological Profile of Patients with Sickle Cell Disease in the Acholi Sub-Region, Uganda.
  13. Unveiling Bone Health in Sickle Cell Disease: A Comprehensive Analysis of Bone Mineral Density.
  14. Physiologically Based Pharmacokinetic Modelling of Hydroxyurea in Patients with Sickle Cell Disease: A Special Focus on Lactating Women and Breastfed Infants to Inform Safe Dosing and Breastfeeding Strategies.
  15. Alterations of Plasma Metabolites Associated with Sickle Cell Trait.
  16. Systematic Review of Non-Coding Genomic Variants in Globin and Non-Globin Clusters and Their Impact on Phenotypic Severity in Thalassemia and Sickle Cell Disease.
  17. Slowing the cell cycle to increase fetal hemoglobin.
  1. Front Immunol. 2026 ;17 1796628
    Editorial: Unraveling inflammatory pathways in sickle cell disease: molecular, cellular and translational insights.
    Nicola Conran, Subarna Chakravorty, Renata Sesti-Costa.
      
    Keywords:  endothelial cells; inflammation; leukocytes; pathophysiology; sickle cell anemia; sickle cell disease
    DOI:  https://doi.org/10.3389/fimmu.2026.1796628
  2. Haematologica. 2026 Feb 26.
    Haploidentical transplantation in sickle cell disease: toward donor availability for all patients.
    Valeria Maria Pinto, Emanuele Angelucci.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300681
  3. Blood Cells Mol Dis. 2026 Feb 18. pii: S1079-9796(26)00010-0. [Epub ahead of print]118 102987
    Inflammatory markers in sickle cell disease during vaso-occlusive crisis.
    Kamal Kumar Meher, Pradeep Kumar Mohanty, Satyabrata Meher.
      Sickle cell disease (SCD) is a monogenic blood disorder in which vaso-occlusive crises (VOC) are the main cause of hospitalization. Along with vascular adhesion, inflammation plays a central role in VOC. This study compared inflammatory and hematological markers in SCD patients during VOC and steady state, examined their association with outcomes such as hospital stay, acute chest syndrome (ACS), and mortality, and evaluated the impact of hydroxyurea. A total of 109 VOC patients admitted to the Department of General Medicine, VIMSAR, and 40 steady-state patients attending the outpatient clinic were included. Hematological (HbF, HbS, hemoglobin, WBC, neutrophils, platelets), biochemical (bilirubin, AST, ALT, urea, creatinine), and inflammatory markers (IL-6,CRP, ferritin, LDH, ESR) were measured. Data were analyzed using GraphPad Prism; comparisons were made by unpaired t-test and correlations by Pearson analysis. VOC patients showed significantly lower hemoglobin and higher WBC and neutrophil counts compared to controls. Inflammatory markers were markedly elevated during VOC: IL-6 (41.95 vs2.1 pg/mL), CRP (61.34 vs3.2 mg/L), ferritin (847.6 vs116.7 ng/mL), and LDH (1151.7 vs719.5 U/L). Platelet count and ESR did not differ significantly. Hydroxyurea use was associated with lower inflammatory marker levels. Inflammation strongly influences VOC severity and outcomes, and hydroxyurea mitigates this effect. Routine monitoring of inflammatory markers may support predicting course and management in SCD.
    Keywords:  Inflammatory marker; Sickle cell disease; Vaso Occlusive Crisis
    DOI:  https://doi.org/10.1016/j.bcmd.2026.102987
  4. Blood Adv. 2026 Feb 24. 10(4): 1278-1280
    One cell at a time: HbF distribution in sickle cell disease.
    Eugene Khandros, Martin H Steinberg.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025018293
  5. Blood Adv. 2026 Feb 24. 10(4): 1168-1178
    Comprehensive analysis of complement activation in a hydroxyurea-treated patient cohort with sickle cell disease.
    Daniel Diatlov, Arlette Bohorquez-Hernandez, Melanie Kirby-Allen, Christoph Licht.
       ABSTRACT: Sickle cell disease (SCD) is an understudied, life-threatening genetic disorder affecting ∼300 000 infants yearly with limited treatment options. The complement system, a critical part of innate immunity, has emerged as a contributor to SCD pathophysiology, thus presenting a potential new treatment target. Our aim was to assess complement activity in children with SCD receiving hydroxyurea (HU) therapy during vaso-occlusive crisis (VOC) and steady state. Blood samples were collected from 46 pediatric patients with SCD during VOC (early and late) and steady state, with control samples from healthy volunteers. Clinical data were obtained from patient records, and patient heme levels were measured using colorimetric assay. Complement deposition on endothelial cells (ECs) was quantified using high-throughput automated immunofluorescence imaging. Complement protein concentration was measured using enzyme-linked immunosorbent assay and multiplex assays. We found that, in vitro, heme drove C3b and C5b-9 deposition on ECs. Patients had increased heme levels during both VOC and steady state compared with healthy controls. However, complement activation correlated with total hemoglobin (Hb) concentration in patients during steady state, but not heme levels. C5b-9 deposition on ECs was significantly higher in patients during early crisis compared with late crisis, suggesting heightened complement activity early in VOC, with C5b-9 deposition also strongly correlating with circulating soluble C5b-9 levels. A significant increase in the C3b/C3 ratio further indicated early complement activation during VOC. In conclusion, complement activity is likely highest in early VOC in patients with SCD, and presents a critical potential treatment target, but is overall attenuated by HU therapy despite elevated heme or Hb levels.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016958
  6. Am J Hematol. 2026 Feb 27.
    Genetic Contribution to Asthma Informs Acute Chest Syndrome Pathophysiology and Risk Stratification.
    Sara El Aouhel, Vanessa Bellegarde, Stennio Da Silva Faria, Tristan St-Laurent, Estelle Lecluze, Anne-Laure Pham Hung d'Alexandry d'Orengiani, Frédéric Galactéros, Pablo Bartolucci, Marc-André Legault, Guillaume Lettre, Thomas Pincez.
      Acute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) occurring in ~50% of patients, some presenting frequent episodes. We lack tools to identify patients at high risk of ACS occurrence or frequent episodes. Epidemiological studies have found an association between asthma and ACS, but whether this link is causal is unclear. We used polygenic scores (PGS) to analyze whether the genetic propensity for asthma was associated with ACS and could be used to stratify the risk of ACS. We identified that PGS for asthma (PGSasthma) was associated with ACS rate (number of episodes per year), but not ACS occurrence, in both the CSSCD (n = 1278) and the GEN-MOD (n = 406) prospective SCD cohorts, independently of fetal hemoglobin (HbF) (β = 0.17, standard error = 0.06, p = 0.006). This effect was most pronounced in patients with low HbF levels. Combining PGSasthma and HbF identified a population at high risk of frequent ACS after a first episode: individuals within the highest PGSasthma quintile and the lowest HbF quintile. Finally, we found that the genetic correlation between these two conditions only partially overlapped. This suggests that genetically determined asthma is not the unique contributor to the genetic propensity for ACS and that other genetic determinants may also play a role. In sum, our results suggest that patients with a high genetic propensity for asthma are prone to frequent ACS if not protected by high HbF levels. Combining PGSasthma and HbF may allow identifying patients at high risk of frequent ACS after a first episode for personalized management.
    Keywords:  acute chest syndrome; asthma; polygenic score; risk stratification; sickle cell disease
    DOI:  https://doi.org/10.1002/ajh.70262
  7. Indian J Hematol Blood Transfus. 2026 Mar;42(2): 463-471
    Impact of HBS1L-MYB Gene Single Nucleotide Polymorphisms on Fetal Hemoglobin Expression in Moroccan Sickle Cell Anemia Children: Preliminary Results.
    Kenza Arbai, Fatima Zahra Alaoui Ismaili, Zeineb Zian, Amale Essayah, Chourouk Mansour, Amina Lhoussni, Seddik Belahsen, Naima Ghailani Nourouti, Amina Barakat, Mohcine Bennani Mechita.
      Fetal hemoglobin (HbF) expression is a key modifier of sickle cell disease (SCD) severity, and the HBS1L-MYB intergenic region is a critical regulator of HbF levels. However, the impact of HBS1L-MYB polymorphisms and HbF levels in Moroccan populations remains underexplored. This work aimed to investigate the population-specific distribution of three HBS1L-MYB polymorphisms (rs28384513, rs4895441, and rs9402686) in 160 Moroccan children, including 80 with SCD (1-15 years) and 80 healthy controls. The SCD group was further divided into two groups based on HbF levels (< 15% and ≥ 15%). DNA genotyping was performed using PCR-RFLP analysis. Retrospective demographic and hematological data were collected to assess the association between these SNPs and HbF levels. Significant associations were found between rs28384513 and red blood cell count (p = 0.009), rs4895441 and mean corpuscular haemoglobin (p = 0.02), and rs9402686 with both hemoglobin (p = 0.001) and HbF levels (p = 0.003), confirming the significant influence of this SNP on HbF expression. These findings highlight the beneficial effect of rs9402686 on HbF expression. Investigating the large and genetically diverse cohort of Moroccan SCD will be essential for a deeper understanding of the molecular mechanisms underlying these polymorphisms and for identifying new disease modifier genes.
    Keywords:  Anemia; Fetal hemoglobin; HBS1L-MYB; Hematological features; Morocco; Sickle cell disease
    DOI:  https://doi.org/10.1007/s12288-025-02102-y
  8. Cells. 2026 Feb 10. pii: 326. [Epub ahead of print]15(4):
    Rethinking Sickle Cell Disease as a Systemic Vasculopathy.
    Mariana DuPont, Najibah A Galadanci, Rushil V Patel, Jeffrey Lebensburger, Julie Kanter.
      Sickle cell disease (SCD) is the most common inherited clinically relevant blood disorder. Although a deceptively simple monogenetic disorder, the associated complications have multiple downstream effects. In this review, we explore the many facets of SCD, with a particular focus on its impact on the vascular system. Despite progress in understanding the underlying mechanisms of SCD, including Hemoglobin S polymerization, microvascular occlusion, and inflammation, there are still many questions surrounding the condition, especially predicting which affected individuals will acquire specific complications in order to personalize treatments. While current standard of care treatments, including hydroxyurea and chronic red blood cell transfusions, have been proven to be disease-modifying, newer therapies like crizanlizumab and voxelotor have only proven to manage symptoms. Newer gene therapies have been approved; however, it is not clear what impact these will have long-term on the end-organ complications of SCD. There is still a significant need to understand how we optimize and personalize therapies to improve outcomes for patients. This review highlights the importance of recognizing SCD as a vascular disease to understand its multi-organ complications and heterogeneity of effects.
    Keywords:  Sickle cell disease; multi-organ complications; vascular system
    DOI:  https://doi.org/10.3390/cells15040326
  9. Haematologica. 2026 Feb 26.
    Three-year safety, efficacy, and renal outcomes of mitapivat treatment in sickle cell disease: results from the phase 2 open-label study.
    Geoffrey Z L Kuppens, Maria Armila D Ruiz, Myrthe J Van Dijk, Minke A E Rab, Cleo Derichs, Joline Saes, Anita W Rijneveld, Marjon H Cnossen, Erfan Nur, Bart J Biemond, Marije Bartels, Santosh L Saraf, Eduard J Van Beers.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.289105
  10. Indian J Hematol Blood Transfus. 2026 Mar;42(2): 487-493
    Sickle Cell Disease in Central India: Haematological and Clinical Insights from a Large Cohort of Patients.
    Nagaraj Jaganathasamy, Sayali Tiwari, Sneha Dadheech, Dipti Soni Sankhari, Nikhil Shinde, Vinod Umare, Pallavi Thaker, Kalpita Gawit, Prabhakar Kedar, Malay B Mukherjee, Manisha Madkaikar.
      Sickle cell disease (SCD) is an inherited blood disorder that affects haemoglobin. Understanding the variability in the presentation of SCD is important for effective disease management. The present study is a cross-sectional analysis of a cohort of 752 SCD patients during 2016-2020, collected as routine institutional data from the Vidarbha region of central India, undertaken to explore the haematological, molecular and clinical features. Among the 752 SCD patients, 85.8% were SS, and 13.8% were S-β thal while the remaining 0.7% were the HbS-D Punjab variant. The median age of the patients was 17 (IQR: 9-27) years. Among them, 41.4% belonged to the scheduled caste and 17.8% belonged to the scheduled tribe. Common clinical presentations showed hospitalizations (51.3%), blood transfusions (32.4%), febrile episodes (50.7%), acute chest syndrome (29.5%), painful severe crisis (7.5%), and avascular necrosis (AVN) (4.2%). Haematological findings revealed that S-β thal has lower MCV, MCH and MCHC and higher RBC counts compared to SS. Only 24.5% of patients reported consumption of hydroxyurea (HU) regularly. Haemoglobin levels were found to be significantly (P < 0.05) higher in patients receiving HU. Additionally, higher HbF (%) and lower HbS (%) were observed in patients consuming HU. The Xmn1 polymorphism was determined in 342 SCD patients. Out of that 298 (86.6%) patients were homozygous (+/+) and 44 (13.4%) were heterozygous (+/-). The HbF% levels were significantly higher (P = 0.04) in those patients with Xmn1 homozygous (+/+) as compared to the patients with heterozygous (+/-) in S-β thal. During this study course, 21 SS disease patients lost their lives. Our study offers realistic insights into the haematological, clinical and molecular spectrum of a cohort of SCD from the Vidarbha region. The clinical course of the disease is influenced by many factors, such as HbF levels, Xmn polymorphism and HU consumption etc., The study highlights the suboptimal use of HU among the patients. HU has shown an improved clinical course, and its coverage needs to be increased. The comparison of age group-wise distribution of SCD patients and the general population in younger and older age groups reflects early mortality in SCD patients.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-025-02262-x.
    Keywords:  Clinical outcomes; Hematological parameters; Hydroxyurea; Molecular parameters; Mortality; Sickle cell disease
    DOI:  https://doi.org/10.1007/s12288-025-02262-x
  11. Am J Hematol. 2026 Feb 27.
    Diagnosis and Management of Acute Chest Syndrome in Children With Sickle Cell Disease.
    Thomas C Fisher-Heath, Colin Rogerson, Benjamin Nti, Patrick T McGann, Matthew Hays, Seethal A Jacob.
      
    Keywords:  acute chest syndrome; imaging; pediatrics; sickle cell disease
    DOI:  https://doi.org/10.1002/ajh.70260
  12. J Blood Med. 2026 ;17 558610
    Haematological Profile of Patients with Sickle Cell Disease in the Acholi Sub-Region, Uganda.
    Silvia Awor, Jimmyy Opee, Denis Ocaya, Benard Abola, Geoffrey Maxwell Malinga, Christine Oryema, Beatrice Arwenyo, Acaye Ongwech, Proscovia Nnamuyomba, Jackie Epila, David Musoke.
       Background: Sickle cell disease (SCD) is a genetic blood disorder most prevalent in Eastern and Western Africa. With the high prevalence of SCD in northern Uganda, we set out to document the haematological profile of patients with SCD in Acholi sub-region of northern Uganda.
    Methods: This was a cross-sectional study at Gulu University Teaching Hospitals from February to May 2025. Patients with SCD gave blood, which was analysed at GRRH, and the results were shared with their healthcare providers. Logistic regression was done to determine the association between the haematological parameters and hydroxyurea use.
    Results: Four hundred eighteen blood samples were analysed. The mean age of the participants was seven years of age, and the median was 5 years of age, ranging from 1 to 28 years of age. About 95% of participants had anaemia, 92.1% erythropenia, and 92.6% low haemtocrit levels. Meanwhile, 47.9% of participants had leucocytosis and 49.1% thrombocytosis. Hydroxyurea use was associated with a normal platelet count (OR=0.35, 95% CI 0.18-0.65, p-value=0.001).
    Conclusion: In patients with sickle cell disease, there were increased white blood cells, platelets, and low red blood cells. That may reflect increased haemolytic activities that destroy the sickled red blood cells in low oxygen tension. Hydroxyurea use was associated with normal platelet counts.
    Keywords:  Africa; Uganda; acholi sub-region; full haemogram; sickle cell disease
    DOI:  https://doi.org/10.2147/JBM.S558610
  13. Indian J Hematol Blood Transfus. 2026 Mar;42(2): 456-462
    Unveiling Bone Health in Sickle Cell Disease: A Comprehensive Analysis of Bone Mineral Density.
    Sudem Narzari, Anupam Dutta, Ajit Kumar Pegu, Paramananda Taye, Luish Borboruah, Dipjyoti Boruah.
      Sickle Cell Disease is a well-known haemoglobinopathy affecting a substantial load of population across the globe. Although mainly characterized by anaemia, the overall effects of the disease are not just limited to the haematological system and in fact involves the bones, renal and endocrine organs. The repeated Vaso-occlusive episodes in SCD imparts a negative impact on bone mineral density of the patients and affects the bone growth and metabolism. The study aims to evaluate the bone mineral density in patients with sickle cell disease and as well as establishing potential correlations between bone mineral density and the clinical manifestations of the disease. The present study was conducted in the Dept of Medicine, Assam Medical College & Hospital on 70 sickle cell disease patients. Detailed clinical history was taken and other relevant physical examinations and investigations like anthropometric measurements, routine haematological investigations and bone densitometry using Dual Energy X-ray Absorptiometry (DEXA) were done. Data were represented in appropriate format and statistical analysis was performed using SPSS and Microsoft Excel. Statistical significance was analysed by independent t test and chi square test. Out of the total of 70 participants of the study there were 26 male and 44 female participants. The mean age of patients was 24.72 years and majority of patients belonged to the tea tribe community. Based on DEXA scan, 45 patients (64.3%) were having low BMD defined as either osteopenia or osteoporosis. The prevalence of low BMD in the present study was higher at lumbar spine compared to neck of femur. Low BMD was significantly correlated with low BMI (p<0.001), low haemoglobin (p=0.003), low calcium (p=0.001) and low ferritin level (p=0.001). There is an intricate interplay between low BMD in Sickle Cell Disease and various clinical parameters, revealing strong associations with low Body Mass Index, diminished haemoglobin levels, reduced calcium levels, and elevated serum ferritin levels. This emphasizes the need for comprehensive management strategies addressing nutritional, haematological, and metabolic factors to optimize bone health in this patient population.
    Keywords:  Bone mineral density; Calcium; DEXA; Osteoporosis; Sickle cell disease
    DOI:  https://doi.org/10.1007/s12288-025-02033-8
  14. Pharmaceuticals (Basel). 2026 Jan 27. pii: 220. [Epub ahead of print]19(2):
    Physiologically Based Pharmacokinetic Modelling of Hydroxyurea in Patients with Sickle Cell Disease: A Special Focus on Lactating Women and Breastfed Infants to Inform Safe Dosing and Breastfeeding Strategies.
    Khaled Abduljalil, Neel Deferm, Anna Murphy, Iain Gardner.
      Background/Objectives: Hydroxyurea is currently the standard disease-modifying therapy for reducing sickle cell disease (SCD) complications; however, drug labels currently advise discontinuation of breastfeeding during hydroxyurea therapy due to limited human data on the risk of hydroxyurea exposure in breastfed neonates. Methods: A physiologically based pharmacokinetic (PBPK) model for hydroxyurea was built and verified with data from non-lactating adult patients with SCD. The model was then extended to predict hydroxyurea in nursing and in paediatric populations. Predictions were compared to the observed data. Results: The PBPK model predictions for hydroxyurea pharmacokinetics described the observed data in both adult and paediatric subjects with SCD. Observed concentration profiles were within the 5th-95th prediction intervals, and predicted PK parameters were within 2-fold of the observed values. The predicted milk-to-plasma ratio was 0.8. Neonatal exposure to hydroxyurea via breast milk as a percentage of maternal exposure increased from 0.6% at 1 day to 10% at the 4th week postpartum before declining to 5%, 3%, and 2% at 6, 9, and 12 months postpartum, respectively. Conclusions: About 56% of total milk hydroxyurea exposure is within the first 3 h of post-maternal dose. Disposal of this early milk would reduce the exposure of breastfed children. The reduction in exposure is especially pronounced around the first 1 month postpartum. Lactation PBPK models offer a physiological approach to assess real-life scenarios that are difficult to investigate in clinical studies and provide useful results for future clinical study design and clinical recommendations. This was exemplified with hydroxyurea in the current work.
    Keywords:  PBPK; hydroxyurea; lactation; neonates; paediatric; pharmacokinetics; sickle cell disease
    DOI:  https://doi.org/10.3390/ph19020220
  15. Clin J Am Soc Nephrol. 2026 Feb 27.
    Alterations of Plasma Metabolites Associated with Sickle Cell Trait.
    Yanwei Cai, Aditya Surapaneni, Ana Gabriela Vasconcelos, Mari Johnson, Li Hsu, Wei Sun, Charles Kooperberg, Bing Yu, Wan-Jin Yeo, Paul L Auer, Morgan E Grams, Nora Franceschini, Laura M Raffield, Alex P Reiner.
       BACKGROUND: Sickle cell trait (SCT) is the heterozygous carrier state for sickle cell disease (SCD) and is common among individuals of African ancestry. While SCT is a known risk factor for chronic kidney disease and end-stage kidney disease (ESKD), the mechanisms underlying this phenotypic association have not been fully characterized. We utilized metabolomic profiling to gain insight into the pathobiology of SCT.
    METHODS: We used a nontargeted metabolomics approach (Metabolon Global Discovery Panel) to measure baseline plasma levels of 851 metabolites in 986 older Black or African American women with SCT (mean age 61 ± 7 years) compared to 998 age- and race-matched controls without SCT from the prospective Women's Health Initiative (WHI) study. Age-adjusted linear regression was used to assess the association between metabolite levels and SCT. Replication was performed in an independent sample of 1,070 African American men and women (including 70 with SCT) from the Atherosclerosis Risk in Communities (ARIC) study.
    RESULTS: In age-adjusted models, 69 metabolites were significantly associated with SCT in WHI after correction for multiple testing. Many of the SCT-associated metabolites are markers of kidney glomerular filtration (eGFR) and/or related to oxidative stress metabolic pathways known to be altered in SCD homozygotes. Of the 64 SCT-associated metabolites available for replication, 25 or 39% were replicated in the ARIC study. Inclusion of SCT-associated metabolites was associated with significantly better risk prediction of incident ESKD in WHI among SCT individuals compared with a baseline model adjusted for age + estimated glomerular filtration rate (eGFR).
    CONCLUSIONS: We identified and replicated metabolites associated with SCT, many of which are related to eGFR and/or pathways altered in SCD (e.g., oxidative stress, membrane remodeling). These results suggest that plasma metabolomic profiling may be useful in ESKD risk stratification for individuals with SCT, meriting validation in larger cohorts.
    DOI:  https://doi.org/10.2215/CJN.0000001015
  16. J Clin Med. 2026 Feb 09. pii: 1345. [Epub ahead of print]15(4):
    Systematic Review of Non-Coding Genomic Variants in Globin and Non-Globin Clusters and Their Impact on Phenotypic Severity in Thalassemia and Sickle Cell Disease.
    Abeer M Al-Subaie, J Francis Borgio.
      Background: Haemoglobinopathies such as beta-thalassemia (β-thal), alpha-thalassemia (α-thal) and sickle cell disease (SCD) are characterised by pathogenic gene variations (mutations) in the globin genes. Patients with haemoglobinopathies have the same disease-causing coding variations with very different disease phenotypes, from requiring blood transfusions to being non-symptomatic. The gap between the expected clinical outcomes based on primary coding mutations (the genotype) and the actual observed symptoms (the phenotype) often remains unexplained. We refer to the contribution of secondary genetic modifiers-specifically, non-coding variants of the genome that alter globin gene expression and pathophysiology-as the "missing heritability" of the clinical presentation [Primary Mutation + Missing Heritability (Non-Coding Variants) = Actual Clinical Phenotype]. Objectives: This systematic review aims to find evidence connecting genetic differences outside of the protein-coding region, as in promoters, enhancers or untranslated regions (UTRs), to the clinical severity (phenotype) of beta-thalassemia, alpha-thalassaemia and SCD. We summarise the molecular basis of phenotypic variation among haemoglobinopathy patients with identical variations to reveal their missing heritability and to enhance our understanding of prognostic strategies. Methods: This systematic review was performed in accordance with the PRISMA 2020 guidelines. We used search terms related to haemoglobinopathies, non-coding variation, SNP, promoters, enhancers and clinical severity to search major databases (PubMed and Google Scholar) as of October 2025. A total of 527 (out of 572) abstracts were fit for initial screening to identify the eligible reports. Due to heterogeneity in study designs and reported outcomes, findings were synthesised descriptively and grouped by variant mechanism (cis-acting and trans-acting). The final analysis included 89 articles that demonstrated a direct association between a non-coding genomic variant and a quantitative measure of clinical severity. Results: Two main groups of non-coding variants (NCVs) that modulate foetal haemoglobin (HbF) induction were identified. The first major group comprises cis-acting variants within globin gene clusters (HBG2 promoter XmnI polymorphism, HBB promoter mutations and α-globin enhancer variants), while the second major group comprises trans-acting quantitative trait loci (QTLs) (BCL11A and HBS1L-MYB loci). Non-globin NCVs in the UGT1A1 promoter were also found to influence the severity measures in β-thal and SCD. NCVs primarily alter the binding of transcription factors and the looping dynamics of chromatin, modulating the α/β chain balance ratio and γ-globin repression. The XmnI polymorphism is the most prominent cis-acting modifier associated with β-thal intermedia. The promoter polymorphisms in TNF-α and VCAM1 are associated with vascular complications in SCD. Conclusions: NCVs are fundamental when determining the clinical measures of haemoglobinopathies, in addition to coding variants. NCV screening should be integrated for clinical prognosis for the accurate prediction of haemoglobinopathy severity and associated high-risk complications. NCVs may represent promising targets for next-generation gene editing and therapeutic intervention strategies aimed at modifying the severity of β-thal, α-thal and SCD.
    Keywords:  emerging modifiers; foetal haemoglobin; globin gene cluster; missing heritability; non-coding variants; phenotypic severity; sickle cell disease; thalassemia
    DOI:  https://doi.org/10.3390/jcm15041345
  17. Blood. 2026 Feb 26. 147(9): 911-912
    Slowing the cell cycle to increase fetal hemoglobin.
    Patrick G Gallagher.
      
    DOI:  https://doi.org/10.1182/blood.2025032404
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