The impact of the rs887829 C>T genetic polymorphism of UGT1A1 on the response to deferasirox in Iraqi thalassaemia patients
DOI:
https://doi.org/10.60988/p.v37i2S.202Keywords:
thalassaemia; rs887829; C>T; UGT1A1; deferasirox; polymorphismAbstract
Beta thalassaemia major, also known as transfusion-dependent thalassaemia (TDT), is an autosomal recessive genetic disorder necessitating lifelong blood transfusions. Due to the absence of physiological iron excretion, patients require iron chelation therapy. Despite treatment with the oral iron chelator deferasirox (DFX), many patients exhibit elevated serum ferritin (SF) levels. UDP-glucuronosyltransferase 1A1 (UGT1A1) – the principal gene of the UGT1 enzyme family – plays a central role in DFX metabolism. This cross-sectional study was conducted at the Karbala Hereditary Blood Diseases Center between November 2023 and April 2024. A total of 96 Iraqi patients with TDT (aged 8–39 years) were treated with DFX at a daily dose of 30–40 mg/kg for a minimum of three months. Their SF levels, serum erythroferrone levels, and liver and kidney functions were assessed. Genotyping of the rs887829 C>T single nucleotide polymorphism (SNP) in UGT1A1 was performed using allele-specific polymerase chain reaction. The genotype frequencies for rs887829 were: CC (79.2%), CT (13.5%), and TT (7.3%). The wild-type (C) allele frequency was 0.86, compared to 0.14 for the mutant (T) allele. Patients with the TT genotype had significantly higher total serum bilirubin (TSB) levels compared to those with CC or CT genotypes (p=0.03). The rs887829 SNP was associated with increased TSB levels and may contribute to the development of hyperbilirubinaemia in Iraqi patients with TDT.
References
1. Rao E., Kumar Chandraker S., Misha Singh M., Kumar R. Global distribution of β-thalassemia mutations: an update. Gene 896, 148022, 2024. DOI: 10.1016/j.gene.2023.148022
2. Cunningham M.J., Macklin E.A., Neufeld E.J., Cohen A.R.; Thalassemia Clinical Research Network. Complications of beta-thalassemia major in North America. Blood 104(1), 34–39, 2004. DOI: 10.1182/blood-2003-09-3167
3. Cappellini M.D., Cohen A., Eleftheriou A., Piga A., Porter J., Taher A. Guidelines for the Clinical Management of Thalassaemia. Second Revised Edition. Nicosia: Thalassaemia International Federation, 2008.
4. Allegra S., De Francia S., Cusato J., Arduino A., Massano D., Longo F., et al. Deferasirox pharmacogenetic influence on pharmacokinetic, efficacy and toxicity in a cohort of pediatric patients. Pharmacogenomics 18(6), 539–554, 2017. DOI: 10.2217/pgs-2016-0176
5. Chen G., Ramos E., Adeyemo A., Shriner D., Zhou J., Doumatey A.P., et al. UGT1A1 is a major locus influencing bilirubin levels in African Americans. Eur. J. Hum. Genet. 20(4), 463–468, 2012. DOI: 10.1038/ejhg.2011.206
6. Steventon G. Uridine diphosphate glucuronosyltransferase 1A1. Xenobiotica 50(1), 64–76, 2020. DOI: 10.1080/00498254.2019.1617910
7. Brittenham G.M., Cohen A.R., McLaren C.E., Martin M.B., Griffith P.M., Nienhuis A.W., et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am. J. Hematol. 42(1), 81–85, 1993. DOI: 10.1002/ajh.2830420116
8. Shin H.J., Kim J.Y., Cheong H.S., Na H.S., Shin H.D., Chung M.W. Functional study of haplotypes in UGT1A1 promoter to find a novel genetic variant leading to reduced gene expression. Ther. Drug Monit. 37(3), 369–374, 2015. DOI: 10.1097/FTD.0000000000000154
9. Cusato J., Allegra S., Massano D., De Francia S., Piga A., D’Avolio A. Influence of single-nucleotide polymorphisms on deferasirox C trough levels and effectiveness. Pharmacogenomics J. 15(3), 263–271, 2015. DOI: 10.1038/tpj.2014.65
10. Kautz L., Jung G., Nemeth E., Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood 124(16), 2569–2574, 2014. DOI: 10.1182/blood-2014-06-584607
