2026-02-27 | 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.
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.
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2026-02-23 | Pulmonary hypertension in beta thalassemia: a prospective cohort study on treatment outcomes and cardiopulmonary function.
Beta thalassaemia, an inherited blood disorder, exhibits a broad range of phenotypes from asymptomatic to severe anaemia. Pulmonary hypertension (PH) is a major complication in thalassaemia patients, significantly impacting morbidity and mortality. This study aimed to assess the clinical condition of thalassaemia patients with PH over the course of one year while receiving treatment in accordance with the guidelines of the European Society of Cardiology (ESC). A prospective cohort study was carried out at Rohani Hospital in Iran from May 2020 to May 2021. The study included patients diagnosed with beta thalassaemia intermedia who also had PH confirmed by echocardiography. Treatment was administered according to ESC guidelines, incorporating vasodilators and other supportive medications. Clinical and laboratory data were gathered, and statistical analyses were conducted. Nineteen patients, with a mean age of 42.57 ± 8.62 years, participated in the study. Treatment resulted in notable improvements in the 6-minute walk test (6MWT) (p < 0.001), reduced proBNP levels (p = 0.016), and a lower E/e' ratio (p = 0.01), suggesting enhanced right ventricular (RV) function. However, there were no significant changes in pulmonary artery pressure (PAP) or RV size. Additionally, repeated blood transfusions were linked to RV dysfunction. Repeated blood transfusions correlate with RV dysfunction in thalassaemia patients with PH. Vasodilatory treatment improves 6MWT, proBNP levels, and E/e' ratio, indicating RV function enhancement. This study underscores the importance of comprehensive management strategies for thalassaemia patients with PH to mitigate associated complications and improve outcomes.
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2025-10-20 | Expression of the FAM132B Gene in Iranian Patients with Beta-Thalassemia
Background: Iron homeostasis is a complex process involving multiple factors. Erythroblasts secrete erythroferrone (ERFE), which affects hepcidin production, thereby enhancing iron uptake. This study aimed to investigate the expression of the ERFE-encoding FAM132B gene in Iranian patients with beta-thalassemia major (BTM) and beta-thalassemia intermedia (BTI). Materials and Methods: A total of 40 BTM and BTI patients and 20 healthy blood donors as a control group were recruited. Total RNA was extracted from whole blood samples, and cDNA was synthesized. Gene expression was quantified using a SYBR Green-based real-time PCR (RT-PCR) assay. Data analysis was performed by the GraphPad Prism program using the one-way ANOVA test. Results: The expression of the FAM132B gene was upregulated in BTI patients compared to BTM patients (p = 0.0151). Despite the higher mRNA fold change in BTI patients, no significant difference was observed in the FAM132B gene expression between beta-thalassemia patients (major and intermedia) and the control group. Conclusion: The expression of the FAM132B gene was different between beta-thalassemia major and intermedia patients. Further studies should be conducted to better elucidate the role of erythroferrone as a potential therapeutic target in patients with beta-thalassemia.
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