Geni modificatori della Beta talassemia e sviluppo di un algoritmo per la predizione della severità clinica

Introduction Many genetic factors influence Beta Thalassemia severity, recessive autosomal disorder with a highly variable phenotype, beyond mutations in the causative Beta-globin gene (chr 11). These factors are Alpha-globin genes defects and Fetal Hemoglobin modulators (HBG2:g.- 158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A gene). Metods In this work we studied an International cohort of 890 Beta Thalassemic patients to build a predictive severity model of the pathology. In order to achieve this goal we characterized 54 genetic variants at these loci robustly associated with the amelioration of Beta Thalassemia phenotype. Subsequently we assessed, using Cox proportional hazard analysis on a training set, the effect of these loci on the age at which patients start regular transfusions. Finally we built a Thalassemia Severity Score and validated it on a testing set. Results Discriminatory power of the model was high (C-index=0.705; R2=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, <0.001). Finally, an automatized online calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the presented 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 suport clinical decisions