{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T12:12:42Z","timestamp":1761653562182,"version":"build-2065373602"},"reference-count":41,"publisher":"Centre for Evaluation in Education and Science (CEON\/CEES)","issue":"7","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/BY\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Biochemistry"],"published-print":{"date-parts":[[2025]]},"abstract":"<jats:p>Background: Serum ferritin (SF) monitors secondary iron overload in beta-thalassemia (b-thalassemia). Transferrin (TRF) has been shown to reverse iron accumulation in experimental models, but its role in transfusion-dependent beta-thalassemia (TDT) patients remains unclear. This study aims to explore the relationship between TRF and SF in TDT patients and to reveal the unique connection between specific genotypes and iron metabolism, providing potential therapeutic targets for clinical practice. Methods: This cross-sectional study includes 817 TDT patients (b0\/b0 genotype: n=560; b0\/b+ genotype: n=257). We use genotype-phenotype analysis and employ logistic regression and restricted cubic spline (RCS) curves to assess the association between TRF and SF. Results: Significant differences were observed between the b0\/b0 and b0\/b+ genotypes in terms of age at first transfusion, transfusion requirements, chelation initiation age, reticulocyte count, red blood cell count, red cell distribution width-coefficient of variation (RDW-CV), fetal haemoglobin (HbF) level, splenomegaly, and SF. b0\/b0 patients presented with more severe clinical phenotypes. SF was significantly associated with TRF, HbF, RDW-CV, and chelation therapy. RCS analysis revealed a dose-response relationship with a negative linear correlation between TRF and SF (OR=0.26, P&amp;lt;0.001), indicating that higher TRF levels are linked to lower SF risk. Conclusions: This study systematically confirms for the first time a significant negative correlation between high TRF levels and high SF risk in TDT patients. This new finding may help clinicians more effectively manage iron overload, especially in patients with different genotypes.<\/jats:p>","DOI":"10.5937\/jomb0-54839","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T04:46:53Z","timestamp":1746593213000},"page":"1575-1589","source":"Crossref","is-referenced-by-count":0,"title":["Impact of transferrin levels on iron accumulation in transfusion-dependent beta-thalassemia: A genotype-specific analysis"],"prefix":"10.5937","volume":"44","author":[{"given":"Yidan","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binbin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yushan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liuhua","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueyan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinquan","family":"Lao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingjiang","family":"Long","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhixiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weijian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deguo","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianyu","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhua","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangmin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"3964","reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Origa R. b-Thalassemia. Genetics in Medicine 2017; 19(6): 609-19. doi:10.1038\/gim.2016.173;","DOI":"10.1038\/gim.2016.173"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Alaithan MA, AbdulAzeez S, Borgio JF . A comprehensive review of the prevalence of beta globin gene variations and the co-inheritance of related gene variants in Saudi Arabians with beta-thalassemia SMJ 2018; 39(4): 329-35. doi:10.15537\/smj.2018.4.21360;","DOI":"10.15537\/smj.2018.4.21360"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Zhu Y, Shen N, Wang X, Xiao J, Lu Y. Alpha and beta-Thalassemia mutations in Hubei area of China. BMC Med Genet 2020; 21(1). doi: 10.1186\/s12881-019-0925-5;","DOI":"10.1186\/s12881-019-0925-5"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Huang Y, Lei Y, Liu R, et al. Imbalance of erythropoiesis and iron metabolism in patients with thalassemia. Int J Med Sci 2019; 16(2): 302-10. doi: 10.7150\/ijms.27829;","DOI":"10.7150\/ijms.27829"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Chauhan W , Shoaib S, Fatma R, Zaka ur Rab Z, Afzal M. Beta thalassemia and the advent of new interventions beyond transfusion and iron chelation. Brit J Clinical Pharma 2022; 88(8): 3610-26. doi: 10.1111\/bcp.15343;","DOI":"10.1111\/bcp.15343"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Zhou X, Huang L, Wu J, et al. Impaired bone marrow microenvironment and stem cells in transfusion-dependent beta-thalassemia. Biomedicine & Pharmacotherapy 2022; 146: 112548. doi: 10.1016\/j.biopha.2021.112548;","DOI":"10.1016\/j.biopha.2021.112548"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Voskou S, Aslan M, Fanis P , Phylactides M, Kleanthous M. Oxidative stress in b-thalassaemia and sickle cell disease. Redox Biology 2015; 6: 226-39. doi: 10.1016\/j.redox.2015.07.018;","DOI":"10.1016\/j.redox.2015.07.018"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica 2020; 105(2): 260-72. doi: 10.3324\/haematol.2019.232124;","DOI":"10.3324\/haematol.2019.232124"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Parmar JH, Mendes P . A computational model to understand mouse iron physiology and disease. PLoS Comput Biol 2019; 15(1): e1006680. doi: 10.1371\/journal.pcbi.1006680;","DOI":"10.1371\/journal.pcbi.1006680"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Li H, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in b-thalassemic mice. Nat Med 2010; 16(2): 177-82. doi:10.1038\/nm.2073;","DOI":"10.1038\/nm.2073"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Shah M, Danish L, Khan NU, et al. 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Cardiac complications and iron overload in beta thalassemia major patients-a systematic review and meta-analysis. Ann Hematol 2019; 98(6): 1323-31. doi: 10.1007\/s00277-019-03618-w;","DOI":"10.1007\/s00277-019-03618-w"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Origa R, Cinus M, Pilia MP , et al. Safety and Efficacy of the New Combination Iron Chelation Regimens in Patients with Transfusion-Dependent Thalassemia and Severe Iron Overload JCM. 2022; 11(7): 2010. doi: 10.3390\/jcm11072010;","DOI":"10.3390\/jcm11072010"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Barrett AN, Saminathan R, Choolani M. Thalassaemia screening and confirmation of carriers in parents. Best Practice & Research Clinical Obstetrics & Gynaecology 2017; 39: 27-40. doi:10.1016\/j.bpobgyn.2016.10.015;","DOI":"10.1016\/j.bpobgyn.2016.10.015"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Yousefi B, Ghamari AA, Soleimanpour H, Karimian A. Red Cell Distribution Width as a Novel Prognostic Marker in Multiple Clinical Studies. Indian Journal of Critical Care Medicine 2019; 24(1): 49-54.doi:10.5005\/jp-journals-10071-23328;","DOI":"10.5005\/jp-journals-10071-23328"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Motta I, Bou-Fakhredin R, Taher AT , Cappellini MD. Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation. Drugs 2020; 80(11): 1053-63. doi: 10.1007\/s40265-020-01341-9;","DOI":"10.1007\/s40265-020-01341-9"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Mettananda S, Higgs DR. Molecular Basis and Genetic Modifiers of Thalassemia. Hematology\/Oncology Clinics of North America 2018; 32(2): 177-91. doi: 10.1016\/j.hoc.2017.11.003;","DOI":"10.1016\/j.hoc.2017.11.003"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood 2011; 118(13): 3479-88. doi: 10.1182\/blood-2010-08-300335;","DOI":"10.1182\/blood-2010-08-300335"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Chen H, Choesang T, Li H, et al. Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation. Haematologica 2015; 101(3): 297-308. doi: 10.3324\/haematol.2015.127902;","DOI":"10.3324\/haematol.2015.127902"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Estev\u00e3o IF, Peitl Junior P , Bonini-Domingos CR. Serum ferritin and transferrin saturation levels in b0 and b+ thalassemia patients. Genet Mol Res 2011; 10(2): 632-9. doi: 10.4238\/vol10-2gmr1016;","DOI":"10.4238\/vol10-2gmr1016"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Rahmani R, Naseri P , Safaroghli-Azar A, Tarighi S, hosseini T, Hojjati MT. Investigation of correlation between H63D and C282Y mutations in HFE gene and serum Ferritin level in beta-thalassemia major patients. Transfusion Clinique et Biologique 2019; 26(4): 249-52. doi: 10.1016\/j.tracli.2019.05.003;","DOI":"10.1016\/j.tracli.2019.05.003"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Elalfy MS, Saber MM, Adly AAM, et al. Role of vitamin C as an adjuvant therapy to different iron chelators in young b thalassemia major patients: efficacy and safety in relation to tissue iron overload. European J of Haematology 2015; 96(3): 318-26. doi: 10.1111\/ejh.12594;","DOI":"10.1111\/ejh.12594"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Atmakusuma TD, Nasution IR, Sutandyo N. Oxidative Stress (Malondialdehyde) in Adults Beta-Thalassemia Major and Intermedia: Comparison Between Before and After Blood Transfusion and Its Correlation with Iron Overload. 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An investigation of the effects of curcumin on iron overload, hepcidin level, and liver function in bthalassemia major patients: A double blind randomised controlled clinical trial. Phytotherapy Research 2018; 32(9): 1828-35. doi: 10.1002\/ptr.6118;","DOI":"10.1002\/ptr.6118"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Mirlohi MS, Yaghooti H, Shirali S, Aminasnafi A, Olapour S. Increased levels of advanced glycation end products positively correlate with iron overload and oxidative stress markers in patients with b-thalassemia major. Ann Hematol 2018; 97(4): 679-84. doi: 10.1007\/s00277-017-3223-3;","DOI":"10.1007\/s00277-017-3223-3"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Al-Hakeim HK, Najm AH, Al-Dujaili AH, Maes M. Major Depression in Children with Transfusion-Dependent Thalassemia Is Strongly Associated with the Combined Effects of Blood Transfusion Rate, Iron Overload, and Increased Pro-inflammatory Cytokines. Neurotox Res 2020; 38(1): 228-41. doi: 10.1007\/s12640-020-00193-1;","DOI":"10.1007\/s12640-020-00193-1"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Zaman BA, Rasool SO, Abdo JM. The effect of erythroferrone suppression by transfusion on the erythropoietin-erythroferrone-hepcidin axis in transfusion-dependent thalassaemia: A pre-post cohort study. Br J Haematol 2023; 201(3): 547-51. doi:10.1111\/bjh.18619;","DOI":"10.1111\/bjh.18619"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"Atmakusuma TD, Tenggara JB. Correlation of Transferrin Saturation and Serum Ferritin with Bone Mass Density in Adult Transfusion Dependent Beta-Thalassemia Patients. J Blood Med 2021; 12: 827-32. Published 2021 Sep 9. doi:10.2147\/JBM.S328547;","DOI":"10.2147\/JBM.S328547"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"Rydstr\u00f6m J. Assay of nicotinamide nucleotide transhydrogenases in mammalian, bacterial, and reconstituted systems. Methods Enzymol 1979; 55: 261-75. doi:10.1016\/0076-6879(79)55030-7;","DOI":"10.1016\/0076-6879(79)55030-7"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"Choudhary F , Rani P , Kotru M, et al. Correlation of T-regulatory Cells and Iron Status in b-Thalassemia Major Patients. Cureus 2023; 15(2): e35084. Published 2023 Feb 16. doi:10.7759\/cureus.35084;","DOI":"10.7759\/cureus.35084"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"AlFadhli S, Salem M, Shome DK, Mahdi N, Nizam R. The Effects of HFE Polymorphisms on Biochemical Parameters of Iron Status in Arab Beta-Thalassemia Patients. Indian J Hematol Blood Transfus 2017; 33(4): 545-51. doi:10.1007\/s12288-016-0775-7;","DOI":"10.1007\/s12288-016-0775-7"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"Ragab SM, Safan MA, Badr EA. Study of serum haptoglobin level and its relation to erythropoietic activity in Beta thalassemia children. Mediterr J Hematol Infect Dis 2015; 7(1): e2015019. 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