A genetic score for the prediction of beta-thalassemia severity

Haematologica. 2015 Apr;100(4):452-7. doi: 10.3324/haematol.2014.113886. Epub 2014 Dec 5.

Abstract

Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R(2)=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P<0.001) and with transfusion dependency status (Area Under the Receiver Operating Characteristic Curve=0.774; P<0.001). Finally, an automatized on-line calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the present results could be helpful in the management of patients, both as a predictive score for screening and a standardized scale of severity to overcome the major-intermedia dichotomy and support clinical decisions.

Publication types

  • Multicenter Study

MeSH terms

  • Blood Transfusion
  • DNA, Intergenic
  • Female
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Variation*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mutation
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Retrospective Studies
  • Severity of Illness Index
  • beta-Globins / genetics*
  • beta-Thalassemia / diagnosis*
  • beta-Thalassemia / genetics*
  • beta-Thalassemia / mortality
  • beta-Thalassemia / therapy

Substances

  • DNA, Intergenic
  • beta-Globins