title: Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion.
abstract: BACKGROUND
  The clinical and hematologic features of β-thalassemia are modulated by different factors, resulting in a wide range of clinical severity. The main factors are the type of disease-causing mutation and the ability to produce α-globin and γ-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of β-thalassemia as assessed by the patients' age at first transfusion.
  
  
  METHODS
  We studied the effect of seven loci in a cohort of 316 Sardinian patients with β(0)-thalassemia. In addition to characterizing the β-globin gene mutations, α-globin gene defects and HBG2:g.-158C>T polymorphism, we genotyped two different markers in the BCL11A gene and three in the HBS1L-MYB intergenic region using single nucleotide polymorphism microarrays, imputation and direct genotyping. We performed Cox proportional hazard analysis of the time to first transfusion.
  
  
  RESULTS
  According to the resulting model, we were able to explain phenotypic severity to a large extent (Harrell's concordance index=0.72; Cox & Snell R(2)=0.394) and demonstrated that most of the model's discriminatory ability is attributable to the genetic variants affecting fetal hemoglobin production (HBG2:g.-158C>T, BCL11A and HBS1L-MYB loci: C-index=0.68, R(2)=0.272), while the remaining is due to α-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population.
  
  
  CONCLUSIONS
  This detailed analysis clarifies the impact of genetic modifiers on the clinical severity of the disease, measured by time to first transfusion, by determining their relative contributions in a homogeneous cohort of β(0)-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with β-thalassemia.
authors.affiliation: Clinica Pediatrica 2a, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Ospedale Regionale Microcitemie ASL8, Cagliari, Italy.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Danjou
authors.forename: Franco
authors.initials: F
authors.lastname: Anni
authors.forename: Lucia
authors.initials: L
authors.lastname: Perseu
authors.forename: Stefania
authors.initials: S
authors.lastname: Satta
authors.forename: Carlo
authors.initials: C
authors.lastname: Dessì
authors.forename: Maria Eliana
authors.initials: ME
authors.lastname: Lai
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Renzo
authors.initials: R
authors.lastname: Galanello
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001803:Blood Transfusion; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D016172:DNA Fingerprinting; D021901:DNA, Intergenic / Q000235:genetics*; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics*; D056426:Genetic Loci; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012097:Repressor Proteins; D012720:Severity of Illness Index; D016019:Survival Analysis; D055542:alpha-Globins / Q000235:genetics; D055544:beta-Globins / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D021901:DNA, Intergenic; D005819:Genetic Markers; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055542:alpha-Globins; D055544:beta-Globins; D005319:Fetal Hemoglobin