title: Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients.
abstract: OBJECTIVE
  Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes.
  
  
  METHODS
  Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies.
  
  
  RESULTS
  We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients.
  
  
  CONCLUSIONS
  These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Constantina
authors.initials: C
authors.lastname: Chalikiopoulou
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Anastasia-Gerasimoula
authors.initials: AG
authors.lastname: Tavianatou
authors.affiliation: Hellenic Open University, Patras, Greece.
authors.forename: Argyro
authors.initials: A
authors.lastname: Sgourou
authors.affiliation: University of Patras, Faculty of Medicine, Department of Internal Medicine, Hematology Division, Patras, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kourakli
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kelepouri
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Chrysanthakopoulou
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Vasiliki-Kaliopi
authors.initials: VK
authors.lastname: Kanelaki
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Mourdoukoutas
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Siamoglou
authors.affiliation: Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Anne
authors.initials: A
authors.lastname: John
authors.affiliation: University of Patras, Faculty of Medicine, Department of Internal Medicine, Hematology Division, Patras, Greece.
authors.forename: Argyris
authors.initials: A
authors.lastname: Symeonidis
authors.affiliation: Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Katsila
authors.affiliation: University of Patras, Faculty of Medicine, Laboratory of General Biology, Patras, Greece.
authors.forename: Adamantia
authors.initials: A
authors.lastname: Papachatzopoulou
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece.|Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: George P
authors.initials: GP
authors.lastname: Patrinos
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D000986:Antisickling Agents / Q000627:therapeutic use*; D001124:Argininosuccinate Synthase / Q000235:genetics*; D016022:Case-Control Studies; D014644:Genetic Variation; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D017086:beta-Thalassemia / Q000150:complications / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000986:Antisickling Agents; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D001124:Argininosuccinate Synthase; D006918:Hydroxyurea
keywords: ASS1; NOS1; NOS2A; cGMP signaling; haplotype; hydroxyurea; nitric oxide; pharmacogenomics; β-thalassemia