title: Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: A study on β-thalassemia and hemoglobin E/β-thalassemia patients in Indonesia.
abstract: OBJECTIVE
  Thalassemia is a monogenic hematologic disease that has the highest prevalence globally. In addition, there is complexity of the genetic background associated with a variety of phenotypes presented among patients. Genetic heterogeneity related to fetal hemoglobin (HbF) production has been reported as an influencing phenotypic factor of β-thalassemia (β-thal). Therefore, this study aimed to find the effect of these genetic modifiers, especially in the XmnI locus, rs11886868, rs766432 (BCL11A), and rs9399137 (HBS1L-MYB), among β-thal and HbE/β-thal patients in Indonesia, according to laboratory and clinical outcomes, including HbF levels and clinical scores. This study was also designed to compare these modifying effects among β-thal and HbE/β-thal patients in Indonesia.
  
  
  METHODS
  A total of 189 patients with genotyping of β-thal and HbE/β-thal were included in this study. The erythrocytes index and Hb electrophoresis measurements were calculated using appropriate methods. The severity of β-thal and HbE/β-thal was classified based on the Mahidol score. Polymorphism of the XmnI locus, rs11886868, rs766432 (BCL11A), and rs9399137 (HBS1L-MYB) was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS) methods.
  
  
  RESULTS
  The distributions of minor allele in the XmnI locus, rs11886868, rs766432, and rs9399137 were 14%, 22%, 19% and 18% respectively. The variation allele in the XmnI locus, rs11886868, and rs766432 showed a significant value for modifying HbF and clinical score in HbE/β-thal patients, but rs9399137 did not demonstrate such features. In β-thal patients, however, no correlation was found for any single-nucleotide polymorphisms and clinical appearance.
  
  
  CONCLUSIONS
  The XmnI locus, rs11886868, and rs766432 have a modifying effect on HbF and clinical score in HbE/β-thal patients in Indonesia, but not in β-thal patients.
authors.affiliation: Department of Molecular Biology, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Central Java, Indonesia. Electronic address: l.rujito@unsoed.ac.id.
authors.forename: Lantip
authors.initials: L
authors.lastname: Rujito
authors.affiliation: Department of Pediatrics, Banyumas General Hospital, Banyumas, Central Java, Indonesia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Basalamah
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Central Java, Indonesia.
authors.forename: Wahyu
authors.initials: W
authors.lastname: Siswandari
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Central Java, Indonesia.
authors.forename: Joko
authors.initials: J
authors.lastname: Setyono
authors.affiliation: Indonesian Red Cross, Banyumas Unit, Purwokerto, Central Java, Indonesia.
authors.forename: Gondo
authors.initials: G
authors.lastname: Wulandari
authors.affiliation: Department of Pediatrics, Sardjito Central General Hospital, Sekip, Yogyakarta, Indonesia.
authors.forename: Sri
authors.initials: S
authors.lastname: Mulatsih
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Yayasan Rumah Sakit Islam (YARSI) University, Cempaka Putih, Jakarta, Indonesia.
authors.forename: Abdul Salam M
authors.initials: AS
authors.lastname: Sofro
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Ahmad Hamim
authors.initials: AH
authors.lastname: Sadewa
authors.affiliation: Department of Pediatrics, Sardjito Central General Hospital, Sekip, Yogyakarta, Indonesia.
authors.forename: Sutaryo
authors.initials: S
authors.lastname: Sutaryo
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D021901:DNA, Intergenic / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism; D056426:Genetic Loci; D006446:Hemoglobin E / Q000378:metabolism*; D006801:Humans; D007214:Indonesia; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D012097:Repressor Proteins; D014172:Transillumination; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics* / Q000473:pathology*
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D021901:DNA, Intergenic; D009687:Nuclear Proteins; D012097:Repressor Proteins; D004247:DNA; D006446:Hemoglobin E; D005319:Fetal Hemoglobin
keywords: BCL11A; HBS1L-MYB; Modifier effect; Thalassemia; XmnI