DOI: https://doi.org/10.14710/jbtr.v4i1.2541

Genetic Background of β Thalassemia Modifier: Recent Update

1Universitas Jenderal Soedirman, Indonesia

2International Medical University Kuala Lumpur, Malaysia

Received: 17 Apr 2018; Published: 31 Jul 2018.
Open Access Copyright (c) 2018 Journal of Biomedicine and Translational Research

Citation Format:
Abstract

Thalassemia has become major health problem among developing countries. Genetic background which contain enormous mutations and variations have lead in clinical problem differences.

The genetic basis of thalassemia, beta specifically, is mutations of the gene encoding the β chain of the hemoglobin (Beta-Globin, HBB). However, today it is known that abnormalities in this gene do not necessarily determine the clinical appearance of β thalassemia patients.

A set of genes has been found that can modify the primary β thalassemia disorder. Secondary modifier contains genes that have been associated with elevated levels of HbF and improvement ratio of α / β globin chain. The genes involved are HBA, HBG, BCL11A, HBS1L-MYB and other cofactor genes regulating erythropoiesis. Tertiary genetic modifier comes from other genes related to the disease severity including iron metabolism, redox activity, and clinical complications. The review aims to provide the latest updates regarding the known β Thalassemia modifier genes and some other genes involved in the changes of the clinical manifestations.

Note: This article has supplementary file(s).

Fulltext View|Download |  Research Instrument
Figure 1. β Globin Gene and Common β Thalassaemia Mutation
Subject
Type Research Instrument
  View (33KB)    Indexing metadata
 Research Instrument
Figure 2. Normal and β thalassemia condition
Subject
Type Research Instrument
  View (49KB)    Indexing metadata
Keywords: thalassemia β thalassemia; genetic modifiers;BCL11A;HBS1L-MYB;XmnI

Article Metrics:

Article Info
Section: Review Articles
Language : EN
Recent articles
The Effect of Eurycoma longifolia Jack on sICAM-1 and eNOS in Rats with High Fat Diet Level of hsCRP Maternal Serum During Puerperium of Severe Preeclampsia The Difference of Integrin ανβ3 Expression, Leukemia Inhibitory Factors and Superoxide Dismutase Serum Concentration in the Provision of Kebar Extract (Biophytum petersianum Klotczh), Metformin, and Their Combination to Mouse models of Endometriosis Genetic Background of β Thalassemia Modifier: Recent Update More recent articles
  1. Thalassemia International Federation. Epidemiology. Available from: http://wwwthalassaemiaorgcy/about-haemoglobin-disorders/beta-thalassaemia/epidemiologyshtml Accessed January 7, 2014. 2014
  2. Angastiniotis M, Vives Corrons J-L, Soteriades ES, Eleftheriou A. The Impact of Migrations on the Health Services for Rare Diseases in Europe: The Example of Haemoglobin Disorders. The Scientific World Journal. 2013;2013:10
  3. Weatherall DJ. Thalassemia as a global health problem: recent progress toward its control in the developing countries. Annals of the New York Academy of Sciences. 2010;1202:17-23
  4. Galanello R, Perseu L, Satta S, Demartis FR, Campus S. Phenotype-genotype correlation in β-thalassemia. Thalassemia Reports. 2011;1:e6
  5. Thein SL. The Molecular Basis of β-Thalassemia. Cold Spring Harbor Perspectives in Medicine. 2013;3
  6. Cao A, Moi P, Galanello R. Recent advances in β-thalassemias. Pediatric reports. 2011;3:e17
  7. Ramos P, Melchiori L, Gardenghi S, Van-Roijen N, Grady RW, Ginzburg Y, et al. Iron metabolism and ineffective erythropoiesis in beta-thalassemia mouse models. Annals of the New York Academy of Sciences. 2010;1202:24-30
  8. Rivella S. The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia. Blood reviews. 2012;26 Suppl 1:S12-5
  9. Tsiftsoglou AS, Vizirianakis IS, Strouboulis J. Erythropoiesis: model systems, molecular regulators, and developmental programs. IUBMB life. 2009;61:800-30
  10. Cao A, Moi P, Galanello R. Recent advances in beta-thalassemias. Pediatric reports. 2011;3:e17
  11. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th edition ed: Oxford, Blackwell Science; 2008
  12. Galanello R, Origa R. Beta-thalassemia. Orphanet Journal of Rare Diseases. 2010;5:11:1-15
  13. Danjou F, Anni F, Perseu L, Satta S, Dessì C, Lai ME, et al. Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion. Haematologica. 2012;97:989-93
  14. Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010;12:61-76
  15. Steinberg MH, Forget BG, Higgs DR, Weatherall DJ. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management (Cambridge Medicine). London: Cambridge University Press; 2009
  16. Honig GR, Adams JG. Human Hemoglobin Genetics: Springer Vienna; 2012
  17. Conti E, Izaurralde E. Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Current opinion in cell biology. 2005;17:316-25
  18. Thein SL. Genetic modifiers of the β-haemoglobinopathies. British journal of haematology. 2008;141:357-66
  19. [Sankaran VG. Targeted Therapeutic Strategies for Fetal Hemoglobin Induction. ASH Education Program Book. 2011;2011:459-65
  20. Chen W, Zhang X, Shang X, Cai R, Li L, Zhou T, et al. The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity. BMC Medical Genetics. 2010;11:31
  21. Guvenc B, Canataroglu A, Unsal C, Yildiz SM, Turhan FT, Bozdogan ST, et al. β-Globin chain abnormalities with coexisting α-thalassemia mutations. Archives of Medical Science : AMS. 2012;8:644-9
  22. Farashi S, Bayat N, Faramarzi Garous N, Ashki M, Montajabi Niat M, Vakili S, et al. Interaction of an α-Globin Gene Triplication with β-Globin Gene Mutations in Iranian Patients with β-Thalassemia Intermedia. Hemoglobin. 2015;39:201-6
  23. Sollaino MC, Paglietti ME, Perseu L, Giagu N, Loi D, Galanello R. Association of α globin gene quadruplication and heterozygous β thalassemia in patients with thalassemia intermedia. Haematologica. 2009;94:1445-8
  24. Origa R, Sollaino MC, Borgna-Pignatti C, Piga A, Feliu Torres A, Masile V, et al. α-Globin Gene Quadruplication and Heterozygous β-Thalassemia: A Not So Rare Cause of Thalassemia Intermedia. Acta haematologica. 2014;131:162-4
  25. Sollaino MC, Paglietti ME, Loi D, Congiu R, Podda R, Galanello R. Homozygous deletion of the major alpha-globin regulatory element (MCS-R2) responsible for a severe case of hemoglobin H disease. Blood. 2010;116:2193-4
  26. Wu M-Y, He Y, Yan J-M, Li D-Z. A novel selective deletion of the major α-globin regulatory element (MCS-R2) causing α-thalassaemia. British journal of haematology. 2016:n/a-n/a
  27. Mettananda S, Gibbons RJ, Higgs DR. α-Globin as a molecular target in the treatment of β-thalassemia. Blood. 2015;125:3694-701
  28. Jouini L, Bibi A, Ouali F, Hadj Fredj S, Ouennich F, Siala H, et al. Contribution of beta-globin cluster polymorphisms to raise fetal hemoglobin levels in normal adults. Molecular biology reports. 2012;39:4619-25
  29. Li Q, Duan Z-J, Stamatoyannopoulos G. Analysis of the mechanism of action of non-deletion hereditary persistence of fetal hemoglobin mutants in transgenic mice. The EMBO Journal. 2001;20:157-64
  30. Gumucio DL, Rood Kl Fau - Blanchard-McQuate KL, Blanchard-McQuate Kl Fau - Gray TA, Gray Ta Fau - Saulino A, Saulino A Fau - Collins FS, Collins FS. Interaction of Sp1 with the human gamma globin promoter: binding and transactivation of normal and mutant promoters
  31. Manchinu MF, Marongiu MF, Poddie D, Casu C, Latini V, Simbula M, et al. In vivo activation of the human δ-globin gene: the therapeutic potential in β-thalassemic mice2014
  32. Green NS, Barral S. Genetic modifiers of HbF and response to hydroxyurea in sickle cell disease. Pediatric blood & cancer. 2011;56:177-81
  33. Bhagat S, Patra PK, Thakur AS. Association between XmnI Polymorphism and HbF Level in Sickle Cell Disease Patients from Chhattisgarh. International Journal of Biomedical Science : IJBS. 2012;8:36-9
  34. Lettre G, Sankaran VG, Bezerra MA, Araujo AS, Uda M, Sanna S, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:11869-74
  35. Nguyen TK, Joly P, Bardel C, Moulsma M, Bonello-Palot N, Francina A. The XmnI (G)gamma polymorphism influences hemoglobin F synthesis contrary to BCL11A and HBS1L-MYB SNPs in a cohort of 57 beta-thalassemia intermedia patients. Blood cells, molecules & diseases. 2010;45:124-7
  36. Cao A, Galanello R, Origa R. Beta-Thalassemia [Updated 2013 Jan 24]. In: Pagon RA AM, Ardinger HH, et al, editor. GeneReviews® [Internet]. Seattle (WA): University of Washington; 2015
  37. Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:11346-51
  38. Mukherjee MB, Nadkarni AH, Gorakshakar AC, Ghosh K, Mohanty D, Colah RB. Clinical, hematologic and molecular variability of sickle cell-beta thalassemia in western India. Indian journal of human genetics. 2010;16:154-8
  39. Gibney GT, Panhuysen CM, So JC, Ma EK, Ha SY, Li CK, et al. Variation and heritability of Hb F and F-cells among β-thalassemia heterozygotes in Hong Kong. American journal of hematology. 2008;83:458-64
  40. Galarneau G, Palmer CD, Sankaran VG, Orkin SH, Hirschhorn JN, Lettre G. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nature genetics. 2010;42:1049-51
  41. Wahidiyat PA, Gatot D, Tjitrasari T, Ringoringo HP, S MN, Taufani RA, et al. Phenotypic diversity in beta-HbE thalassemia patients. Paediatrica Indonesiana. 2006;46:3-4
  42. Menzel S, Jiang J, Silver N, Gallagher J, Cunningham J, Surdulescu G, et al. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood. 2007;110:3624-6
  43. Wahlberg K, Jiang J, Rooks H, Jawaid K, Matsuda F, Yamaguchi M, et al. The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. Blood. 2009;114:1254-62
  44. Farrell JJ, Sherva RM, Chen ZY, Luo HY, Chu BF, Ha SY, et al. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. Blood. 2011;117:4935-45
  45. Jiang Z, Luo H-y, Huang S, Farrell JJ, Davis L, Théberge R, et al. The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) β0-thalassaemia homozygotes. British journal of haematology. 2016;172:958-65
  46. Jiang J, Best S, Menzel S, Silver N, Lai MI, Surdulescu GL, et al. cMYB is involved in the regulation of fetal hemoglobin production in adults. Blood. 2006;108:1077-83
  47. Xu J, Sankaran VG, Ni M, Menne TF, Puram RV, Kim W, et al. Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes & development. 2010;24:783-98
  48. Sankaran VG, Xu J, Orkin SH. Transcriptional silencing of fetal hemoglobin by BCL11A. Annals of the New York Academy of Sciences. 2010;1202:64-8
  49. Sedgewick AE, Timofeev N, Sebastiani P, So JC, Ma ES, Chan LC, et al. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood cells, molecules & diseases. 2008;41:255-8
  50. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:1620-5
  51. Solovieff N, Milton JN, Hartley SW, Sherva R, Sebastiani P, Dworkis DA, et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. Blood. 2010;115:1815-22
  52. Rujito L, Basalamah M, Siswandari W, Setyono J, Wulandari G, Mulatsih S, et al. Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: A study on β-thalassemia and hemoglobin E/β-thalassemia patients in Indonesia. Hematology/Oncology and Stem Cell Therapy. 2016;9:55-63
  53. Masuda T, Wang X, Maeda M, Canver MC, Sher F, Funnell APW, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science (New York, NY). 2016;351:285-9
  54. Danjou F, Francavilla M, Anni F, Satta S, Demartis F-R, Perseu L, et al. A genetic score for the prediction of beta-thalassemia severity. Haematologica. 2015;100:452-7
  55. Arnaud L, Saison C, Helias V, Lucien N, Steschenko D, Giarratana M-C, et al. A Dominant Mutation in the Gene Encoding the Erythroid Transcription Factor KLF1 Causes a Congenital Dyserythropoietic Anemia. American Journal of Human Genetics. 2010;87:721-7
  56. Huang J, Zhang X, Liu D, Wei X, Shang X, Xiong F, et al. Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin. European Journal of Human Genetics. 2015;23:1341-8
  57. Liu D, Zhang X, Yu L, Cai R, Ma X, Zheng C, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of β-thalassemia. Blood. 2014;124:803-11
  58. Balduini CL, Pecci A, Loffredo G, Izzo P, Noris P, Grosso M, et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thrombosis and haemostasis. 2004;91:129-40
  59. Rivella S. β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015;100:418-30
  60. Tanno T, Bhanu NV, Oneal PA, Goh S-H, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096-101
  61. Sumera A, Radhakrishnan A, Baba AA, George E. Review: Beta-thalassemia and molecular chaperones. Blood Cells, Molecules, and Diseases. 2015;54:348-52
  62. Mahmoud HM, Shoeib AA-SH, Abd El Ghany SM, Reda MM, Ragab IA. Study of alpha hemoglobin stabilizing protein expression in patients with β thalassemia and sickle cell anemia and its impact on clinical severity. Blood Cells, Molecules, and Diseases. 2015;55:358-62
  63. Lai MI, Jiang J, Silver N, Best S, Menzel S, Mijovic A, et al. α-Haemoglobin stabilising protein is a quantitative trait gene that modifies the phenotype of β-thalassaemia. British journal of haematology. 2006;133:675-82
  64. Wajcman H, Vasseur C, Pissard S, Baudin-Creuza V. α-Hemoglobin Stabilizing Protein: A Modulating Factor in Thalassemias? Hemoglobin. 2011;35:463-8
  65. Wang Z, Yu W, Li Y, Shang X, Zhang X, Xiong F, et al. Analysis of alpha-hemoglobin-stabilizing protein (AHSP) gene as a genetic modifier to the phenotype of beta-thalassemia in Southern China. Blood cells, molecules & diseases. 2010;45:128-32
  66. Viprakasit V, Tanphaichitr VS, Chinchang W, Sangkla P, Weiss MJ, Higgs DR. Evaluation of alpha hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients with beta thalassemia. Blood. 2004;103:3296-9
  67. Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. The Lancet. 2012;379:373-83
  68. Voskou S, Aslan M, Fanis P, Phylactides M, Kleanthous M. Oxidative stress in β-thalassaemia and sickle cell disease. Redox Biology. 2015;6:226-39
  69. Rujito L, Mulatsih S, Sofro AM. Status of Superoxide dismutase in transfusion dependent thalassaemia. North Am J Med Sci. 2015;7:194-8
  70. Veal E, Day A. Hydrogen Peroxide as a Signaling Molecule. Antioxidants & Redox Signaling. 2011;15:147-51
  71. Waseem F, Khemomal KA, Sajid R. Antioxidant status in beta thalassemia major: A single-center study. Indian J Pathol Microbiol. 2011;54
  72. Kalpravidh RW, Siritanaratkul N, Insain P, Charoensakdi R, Panichkul N, Hatairaktham S, et al. Improvement in oxidative stress and antioxidant parameters in beta-thalassemia/Hb E patients treated with curcuminoids. Clinical biochemistry. 2010;43:424-9
  73. Sclafani S, Calvaruso G, Agrigento, Maggio A, Lo Nigro V, D'Alcamo E. Glutathione S transferase polymorphisms influence on iron overload in β-thalassemia patients. Thalassemia Reports. 2013;3:20
  74. Mannervik B, Awasthi YC, Board PG, Hayes JD, Di Ilio C, Ketterer B, et al. Nomenclature for human glutathione transferases. Biochemical Journal. 1992;282:305-6
  75. Hahn T, Zhelnova E, Sucheston L, Demidova I, Savchenko V, Battiwalla M, et al. A Deletion Polymorphism in Glutathione-S-Transferase Mu (GSTM1) and/or Theta (GSTT1) Is Associated with an Increased Risk of Toxicity after Autologous Blood and Marrow Transplantation. Biology of Blood and Marrow Transplant. 2010;16:801-8
  76. Origa R, Satta S, Matta G, Galanello R. Glutathione S-transferase gene polymorphism and cardiac iron overload in thalassaemia major. British journal of haematology. 2008;142:143-5
  77. Nagy T, Csordás M, Kósa Z, Góth L. A simple method for examination of polymorphisms of catalase exon 9: rs769217 in Hungarian microcytic anemia and beta-thalassemia patients. Archives of biochemistry and biophysics. 2012;525:201-6
  78. Toumba M, Skordis N. Osteoporosis Syndrome in Thalassaemia Major: An Overview. Journal of Osteoporosis. 2010;2010:537673
  79. Kostik MM, Smirnov AM, Demin GS, Mnuskina MM, Scheplyagina LA, Larionova VI. Genetic polymorphisms of collagen type I α1 chain (COL1A1) gene increase the frequency of low bone mineral density in the subgroup of children with juvenile idiopathic arthritis. The EPMA Journal. 2013;4:15-
  80. Pluijm S, van Essen HW, Bravenboer N, Uitterlinden A, Smit J, Pols H, et al. Collagen type I α1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Annals of the Rheumatic Diseases. 2004;63:71-7
  81. Singh K, Agarwal S, Gupta S. An SP1-binding site polymorphism in the COLIAI gene: may be a strong predictor for low bone density in thalassemia major. Gene Therapy and Molecular Biology. 2013;15:112-9
  82. AlFadhli S, Al-Jafer H, Hadi M, Al-Mutairi M, Nizam R. The Effect of UGT1A1 Promoter Polymorphism in the Development of Hyperbilirubinemia and Cholelithiasis in Hemoglobinopathy Patients. PloS one. 2013;8:e77681
  83. aher AT, Musallam KM, Cappellini MD, Weatherall DJ. Optimal management of β thalassaemia intermedia. British journal of haematology. 2011;152:512-23
  84. Taher A, Isma’eel H, Mehio G, Bignamini D, Kattamis A, Rachmilewitz EA, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thrombosis and haemostasis. 2006;96:488-91
  85. Kahn J-E, Veyssier-Belot C, Renier J-L, de Mazancourt P, Peltier J-Y, de Raucourt E. Recurrent thromboembolism in a patient with β-thalassemia major associated with double heterozygosity for factor V R506Q and prothrombin G20210A mutations. Blood Coagulation & Fibrinolysis. 2002;13:461-3
  86. Agapidou A, Theodoridou S, Tegos K, Mandala E, Leukou E, Karakasidou O, et al. Co-Existence of Hereditary Pyrimidine 5’-Nucleotidase Deficiency and Heterozygous α-Thalassemia: A Case Presentation. Turkish Journal of Haematology. 2012;29:434-5
  87. Guimarães JS, Cominal JG, Silva-Pinto AC, Olbina G, Ginzburg YZ, Nandi V, et al. Altered erythropoiesis and iron metabolism in carriers of thalassemia. European journal of haematology. 2015;94:511-8

Last update:

No citation recorded.

Last update:

No citation recorded.