title: Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy.
abstract: OBJECTIVE
  In this study we explored the association between genetic variations in MAP3K5 and PDE7B genes, residing on chromosome 6q23, and disease severity in β-hemoglobinopathy patients, as well as the association between these variants with response to hydroxyurea (HU) treatment. Furthermore, we examined MAP3K5 expression in the context of high fetal hemoglobin (HbF) and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals.
  
  
  METHODS
  For this purpose, we genotyped β-thalassemia intermedia and major patients and healthy controls, as well as a cohort of compound heterozygous sickle cell disease/β-thalassemia patients receiving HU as HbF augmentation treatment. Furthermore, we examined MAP3K5 expression in the context of high HbF and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals.
  
  
  RESULTS
  A short tandem repeat in the MAP3K5 promoter and two intronic MAP3K5 gene variants, as well as a PDE7B variant, are associated with low HbF levels and a severe disease phenotype. Moreover, MAP3K5 mRNA expression levels are altered in the context of high HbF and are affected by the presence of HU. Lastly, the abovementioned MAP3K5 variants are associated with HU treatment efficacy.
  
  
  CONCLUSIONS
  Our data suggest that these MAP3K5 variants are indicative of β-thalassemia disease severity and response to HU treatment.
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Tafrali
authors.forename: Arsinoi
authors.initials: A
authors.lastname: Paizi
authors.forename: Joseph
authors.initials: J
authors.lastname: Borg
authors.forename: Milena
authors.initials: M
authors.lastname: Radmilovic
authors.forename: Marina
authors.initials: M
authors.lastname: Bartsakoulia
authors.forename: Emily
authors.initials: E
authors.lastname: Giannopoulou
authors.forename: Olga
authors.initials: O
authors.lastname: Giannakopoulou
authors.forename: Maja
authors.initials: M
authors.lastname: Stojiljkovic-Petrovic
authors.forename: Branka
authors.initials: B
authors.lastname: Zukic
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Poulas
authors.forename: Eleana F
authors.initials: EF
authors.lastname: Stavrou
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Lambropoulou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kourakli
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Felice
authors.forename: Adamantia
authors.initials: A
authors.lastname: Papachatzopoulou
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Marianthi
authors.initials: M
authors.lastname: Georgitsi
authors.forename: George P
authors.initials: GP
authors.lastname: Patrinos
mesh_terms: D054316:Biomarkers, Pharmacological / Q000378:metabolism; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D054316:Biomarkers, Pharmacological; D012333:RNA, Messenger; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D006918:Hydroxyurea