title: Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala, Arg184Ser and Ser7Ala) and therapeutic response to deferiprone in β-thalassemia major patients.
abstract: Deferiprone is used as a chelation agent in chronic iron overload in β-thalassemia patients. Patients on deferiprone therapy show variable response to this drug in terms of reduction in iron overload as well as adverse drug reactions (ADRs). The pharmacogenetic studies on deferiprone have not carried out in patients with blood disorders in India. Therefore, the present study was carried out to evaluate the three most common nonsynonymous UGT1A6 polymorphisms Thr181Ala (541 A/G), Arg184Ser (552 A/C) and Ser7Ala (19 T/G) and therapeutic response to deferiprone in β-thalassemia major patients. Two hundred and eighty six (286) β-thalassemia major patients were involved in the study. Serum ferritin levels were estimated periodically to assess the status of the iron overload and the patients were grouped into responders and non-responders depending on the ferritin levels. The UGT1A6 2 polymorphisms were detected by PCR-RFLP methods. The association between the genotypes and outcome as well as ADRs was evaluated by Open EPI software. A significant difference was observed in the genotypic distribution of UGT1A6 2 Thr181Ala polymorphism in responders and non-responders. However, there was no difference in the genotypic distribution between patients with and without ADRs. As far as the UGT1A6 2 Arg184Ser polymorphism is concerned, no significant difference was observed between responders and non-responders. Further, evaluating the association of UGT1A6 2 Ser7Ala polymorphism with drug response, there was no significant difference in the genotypic distribution between responders and non-responders. However, there was a significant difference between responders with and without ADRs and non-responders with and without ADRs. In addition to this haplotype analysis was also carried out. However, we did not find any specific haplotype to be significantly associated with the deferiprone response in β-thalassemia major patients.
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad-500016, India; Dr. NTR University of Health Sciences, Vijayawada, A.P., India.
authors.forename: Sneha
authors.initials: S
authors.lastname: Dadheech
authors.forename: A Venkateswara
authors.initials: AV
authors.lastname: Rao
authors.forename: Uzma
authors.initials: U
authors.lastname: Shaheen
authors.forename: Mohammed Dyia
authors.initials: MD
authors.lastname: Hussien
authors.forename: Suman
authors.initials: S
authors.lastname: Jain
authors.forename: A
authors.initials: A
authors.lastname: Jyothy
authors.forename: Anjana
authors.initials: A
authors.lastname: Munshi
mesh_terms: D000293:Adolescent; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000077543:Deferiprone; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007502:Iron Chelating Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019190:Iron Overload / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D012694:Serine / Q000235:genetics; D013912:Threonine / Q000235:genetics; D016896:Treatment Outcome; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*
chemical_list: D007502:Iron Chelating Agents; D007527:Isoenzymes; D011728:Pyridones; D000077543:Deferiprone; D013912:Threonine; D012694:Serine; D001120:Arginine; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D000409:Alanine
keywords: ADRs; Deferiprone; PCM; PCR-RFLP; Pharmacogenetics; Serum ferritin; UDP-glucuronosyltransferases; UGT1A6*2 gene polymorphism; UGTs; WBC; adverse drug reactions; paracetamol; polymerase chain reaction–restriction fragment length polymorphism; white blood cell; β-Thalassemia