The Authority of Gene Modifiers in β-Thalassemia Major and Its Relationship to the Pathophysiology of the Disease
Abstract
β-Thalassemia, an inherited red blood cell disorder, presents a significant health problem worldwide and is caused by defects in the β-globin gene, resulting in the reduction or absence of β-globin chain synthesis. That leads to blood transfusion dependency with its terrible complications. Polymorphisms at position -158 of XmnI-HBG2 on chromosome 11 and BCL11A site on chromosome 2p16 might be linked with elevated hemoglobin F (HbF) appearance, which may, in turn, improve β-thalassemia sternness. This study aims to walk around the amending effects of XmnI and BCL11A loci on HbF levels in Egyptian β-thalassemia patients. Material and Methods. A prospective case-control study of 70 multi-transfused β-thalassemia major patients and 22 controls was performed in the Paediatric hematology unit of Assiut university hospital from June 2019 till April 2021. PCR-RFLP was used to detect single nucleotide polymorphisms at XmnI and BCL11A site loci. Results. XmnI Polymorphism was detected in 9 of 70 patients and associated with higher mean HbF levels (53.48%) than patients without polymorphism (mean Hb level was 42.23%)(P-Value=0.035). The frequency of CT heterozygous genotype was 8 (11.4%), TT homozygous genotype was (1.4%), while the wild genotype CC was detected in 61 (87.1%) of the cases. While BCL11A Polymorphism detected in 21 of 70 patients did not affect either Hb or HbF levels (P-Value =0.26). The TT genotype frequency was 49 (70%), and TC heterozygous genotype was detected in 21 (30 %) of patients. The CC genotype was absent. Conclusion: XmnI -158Gγ polymorphism, but not BCL11A polymorphism, has a modifying effect on both Hb and HbF levels in Egyptian β-thalassaemia major patients. Our research goal is to investigate the frequency of XmnI and BCL11A polymorphism in thalassemia major and investigate the HbF level difference according to the XmnI and BCL11A polymorphism of phenotype group in thalassemia major.
Keywords: β-Thalassemia major, XmnI polymorphism, BCL11A polymorphism.
https://doi.org/10.55463/issn.1674-2974.49.2.21
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RUND D., & RACHMILEWITZ E. b-Thalassemia. New England Journal of Medicine, 2005, 353(11): 1135–1146. https://doi.org/10.1056/nejmra050436
EL-BESHLAWY A, & YOUSSRY I. Prevention of haemoglobinopathies in Egypt. Hemoglobin, 2009, 33(1): 14–20. https://doi.org/10.3109/03630260903346395
TANTAWY A. A. G, ANDRAWES N. G., ISMAEIL A., KAMEL S. A., and EMAM W. Prevalence of XmnlGγ polymorphism in Egyptian patients with b thalassemia major. Annals of Saudi Medicine, 2012;32(5):487–91. https://doi.org/10.5144/0256-4947.2012.487
THEIN S. L. Molecular basis of β thalassemia and potential therapeutic targets. Blood Cells, Molecules and Diseases, 2018, 70: 54-65. http://dx.doi.org/10.1016/j.bcmd.2017.06.001
RAYCHAUDHURI S. Mapping rare and common causal alleles for complex human diseases, Cell, 2011, 147: 57–69. https://doi.org/10.1016/j.cell.2011.09.011
METTANANDA S. Genetic and Epigenetic Therapies for β-Thalassaemia by Altering the Expression of α-Globin Gene. Frontiers in Genome Editing, 2021. https://doi.org/10.3389/fgeed.2021.752278
CAPPELLINI M. D., FARMAKIS D., PORTER J., and TAHER A. Guidelines for the management of transfusion dependent thalassaemia (TDT) 4th Edition. Thalassaemia International Federation, Nicosia, 2021. https://thalassaemia.org.cy/wp-content/uploads/2021/06/GUIDELINE-4th-DIGITAL-BY-PAGE.pdf
RUJITO L., BASALAMAH M., SISWANDARI W., SETYONO J., WULANDARI G., MULATSIH S., SOFRO A. S. M., SADEWA A. H., and SUTARYO S. Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: a study on beta-thalassaemia and haemoglobin E/beta-thalassaemia patients in Indonesia. Hematology/Oncology and Stem Cell Therapy, 2016, 9: 55–63. https://doi.org/10.1016/j.hemonc.2016.02.003
ANUROGO D., BUDI N. Y. P., NGO M.-H. T., HUANG Y.-H., and PAWITAN J. A. Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing. International Journal of Molecular Sciences, 2021, 22(12): 6275. https://doi.org/10.3390/ijms22126275
FADWA S., & AMINA A.-S. XmnI polymorphism: Relation to β-thalassaemia phenotype and genotype in Egyptian Children. Egyptian Journal of Medical Human Genetics, 2015, 16(2): 123-127. http://dx.doi.org/10.1016/j.ejmhg.2014.12.005
NEMATI H., RAHIMI Z., and BAHRAMI G. The XmnI polymorphic site 5′ to the Gγ gene and its correlation to the Gγ: Aγ ratio, age at first blood transfusion and clinical features in b-Thalassaemia patients from Western Iran. Molecular Biology Reports, 2010, 37(1): 159–164. https://doi.org/10.1007/s11033-009-9566-7
ALI N., AYYUB M., KHAN S. A., AHMED S., AHMED S., ABBAS K., MALIK H. S., and TASHFEEN S. Frequency of Gγ-globin promoter_158 (C>T) XmnI polymorphism in patients with homozygous/compound heterozygous beta thalassaemia. Hematology/Oncology and Stem Cell Therapy, 2015, 8: 10–15. https://doi.org/10.1016/j.hemonc.2014.12.004
MIRI-MOGHADDAM E., BAHRAMI S., NADERI M., Bazi A., and KARIMIPOOR M. XmnI-158 GγVariant in B-Thalassaemia Intermediate Patients in South-East of Iran. International Journal of Hematology and Oncology Stem Cell Research, 2017, 11(2): 165–171. https://pubmed.ncbi.nlm.nih.gov/28875012/
AKBARI M. T., IZADI P., IZADYAR M., KYRIACOU K., and KLEANTHOUS M. Molecular basis of thalassaemia intermedia in Iran. Haemoglobin, 2008, 32(5): 462–470. https://doi.org/10.1080/03630260802341851
ARAB A., KARIMIPOOR M., RAJABI A., HAMID M., ARJMANDI S., and ZEINALI S. Molecular characterization of β-thalassaemia intermedia: a report from Iran. Molecular Biology Reports, 2011, 38(7): 4321–4326. https://doi.org/10.1007/s11033-010-0557-5
ADEKILE A. D., AZAB A. F., AL-SHARIDA S. I., AL-NAFISI B. A., AKBULUT N., MAROUF R. A., and MUSTAFA N. Y. Clinical and molecular characteristics of non-transfusion-dependent thalassaemia in Kuwait. Haemoglobin, 2015, 39(5): 320-326. https://doi.org/10.3109/03630269.2015.1053489
SHAMOON R. P., AL-ALLAWI N. A., CAPPELLINI M. D., DI PIERRO E., BRANCALEONI V., and GRANATA F. Molecular basis of beta-thalassaemia intermedia in Erbil province of Iraqi Kurdistan. Haemoglobin, 2015, 39(3): 178–183. https://doi.org/10.3109/03630269.2015.1032415
LAKS K. M., HIRNER C., GRUNER B., COBERLY J., LAZIUK K., and SATHI B. K. Bart's Disease with Coinheritance of Gγ-XmnI and Aγ-Globin Polymorphisms: A Case of Nontransfusion-Dependent Thalassemia. Case Reports in Hematology, 2020: 8869335. https://doi.org/10.1155/2020/8869335
KOSARYAN M., VAHIDSHAHI K., KARAMI H., and EHTESHAMI S. Effect of hydroxyurea on thalassaemia major and thalassaemia intermedia in Iranian patients. Pakistan Journal of Medical Sciences, 2009, 25(1): 74–78. https://www.researchgate.net/publication/242187447_Effect_of_hydroxyurea_on_thalassemia_major_and_thalassemia_intermedia_in_Iranian_patients
CHINELATO I. S., CARROCINI G. C. S., and BONINI-DOMINGOS C. R. XmnI polymorphism frequency in heterozygote beta thalassaemia subjects and its relation to fetal haemoglobin levels. Revista Brasileira de Hematologia e Hemoterapia, 2011, 33(6): 483. https://dx.doi.org/10.5581%2F1516-8484.20110128
HAJ KHELIL A., MORINIE'RE M., LARADI S., KHELIF A., PERRIN P., BEN CHIBANI J., and BAKLOUTI F. XmnI polymorphism associated with concomitant activation of Gc and Ac globin gene transcription on a beta0-thalassaemia chromosome. Blood Cells, Molecules & Diseases, 2011, 46: 133–138. https://doi.org/10.1016/j.bcmd.2010.11.002
SCHECHTER A. Haemoglobin research and the origins of molecular medicine. Blood, 2008, 112(10): 3927–3938. https://doi.org/10.1182/blood-2008-04-078188
BIANCHI N., ZUCCATO C., LAMPRONTI I., BORGATTI M., and GAMBARI R. Fetal hemoglobin inducers from the natural world: A novel approach for identification of drugs for the treatment of beta-thalassemia and sickle-cell anemia. Evidence-based Complementary and Alternative Medicine, 2009, 6: 141–151. https://dx.doi.org/10.1093%2Fecam%2Fnem139
NEISHABURY M., AZARKEIVAN A., and NAJMABADI H. Frequency of Positive XmnI Gγ polymorphism and coinheritance of common alpha thalassaemia mutations do not show statistically significant difference between thalassaemia major and intermedia cases with homozygous IVSII-1 mutation. Blood Cells, Molecules & Diseases, 2010, 44(2): 95–99. https://doi.org/10.1016/j.bcmd.2009.10.007
OBEROI S., DAS R., PANIGRAHI I., KAUR J., and MARWAHA R. K. XmnI-Gγ polymorphism and clinical predictors of severity of disease in β-thalassaemia intermedia. Pediatric Blood & Cancer, 2011, 57(6): 1025–1028. https://doi.org/10.1002/pbc.23175
MONA E.-G., MERVAT K., MARWA A.-H., ERINI M., MOHAMED N. B., and KHORSHIED M. M. Association between BCL11A, HSB1L-MYB and XmnIG-158 (C/T) genetic polymorphisms and haemoglobin F in Egyptian sickle cell disease patients. Annals of Hematology, 2020, 99(10): 2279-2288. https://doi.org/10.1007/s00277-020-04187-z
GALANELLO R., SANNA S., PERSEU L., SOLLAINO M. C., SATTA S., LAI M. E., BARELLA S., UDA M., USALA G., ABECASIS G. R., and CAO A. Amelioration of Sardinian β0 thalassaemia by genetic modifier. Blood, 2004, 114: 3935–3937. https://doi.org/10.1182/blood-2009-04-217901
PAKDEE N., YAMSRI S., FUCHAROEN G., SANCHAISURIYA K., PISSARD S., and FUCHAROEN S. Variability of haemoglobin F expression in haemoglobin EE disease: hematological and molecular analysis. Blood Cells, Molecules & Diseases, 2014; 53: 11–15. https://doi.org/10.1016/j.bcmd.2014.02.005
DADHEECH S., MADHULATHA D., JAINC S., JOSEPH J., JYOTHY A., and MUNSHI A. Association of BCL11A genetic variant (rs11886868) with severity in β-thalassaemia major & sickle cell anaemia. Indian Journal of Medical Research, 2016, 143(4): 449–454. https://doi.org/10.4103/0971-5916.184285
KARIMI M., HAGHPANAH S., FARHADI A., and YAVARIAN M. Genotype-phenotype relationship of patients with β-thalassaemia taking hydroxyurea: a 13-year experience in Iran. International Journal of Hematology, 2012, 95(1): 51–56. https://doi.org/10.1007/s12185-011-0985-6
P. HUANG, S. A. PESLAK, X. LAN, E. KHANDROS, J. A. YANO, M. SHARMA, C. A. KELLER, B. GIARDINE, K. QIN, O. ABDULMALIK, HARDISON R. C., SHI J., and BLOBEL G. A. The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. Blood, 2020, 135(24): 2121–2132. https://doi.org/10.1182/blood.2020005301
BAUER D. E., KAMRAN S. C., LESSARD S., XU J., FUJIWARA Y., LIN C., SHAO Z., CANVER M. C., SMITH E. C., PINELLO L., SABO P. J., VIERSTRA J., VOIT R. A., YUAN G.-C., PORTEUS M. H., STAMATOYANNOPOULOS J. A., LETTRE G., and ORKIN S. H. An erythroid enhancer of BCL11A subject to genetic variation determines fetal haemoglobin level. Science, 2013, 342(6155): 253-257. https://doi.org/10.1126/science.1242088
DANJOU F., ANNI F., and GALANELLO R. Beta-thalassemia: from genotype to phenotype. Haematologica, 2011, 96(11): 1573-1575. https://dx.doi.org/10.3324%2Fhaematol.2011.055962
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