A genetic score for the prediction of beta-thalassemia severity

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...

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Vydáno v:	Haematologica (Roma) Ročník 100; číslo 4; s. 452 - 457
Hlavní autoři:	Danjou, F., Francavilla, M., Anni, F., Satta, S., Demartis, F.-R., Perseu, L., Manca, M., Sollaino, M. C., Manunza, L., Mereu, E., Marceddu, G., Pissard, S., Joly, P., Thuret, I., Origa, R., Borg, J., Forni, G. L., Piga, A., Lai, M. E., Badens, C., Moi, P., Galanello, R.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Italy Ferrata Storti Foundation 01.04.2015
Témata:	beta-Globins - genetics beta-Thalassemia - diagnosis beta-Thalassemia - genetics beta-Thalassemia - mortality beta-Thalassemia - therapy Blood Transfusion DNA, Intergenic Female Genetic Association Studies Genetic Loci Genetic Variation Humans Kaplan-Meier Estimate Life Sciences Male Mutation Phenotype Polymorphism, Single Nucleotide Prognosis Retrospective Studies Severity of Illness Index
ISSN:	0390-6078, 1592-8721, 1592-8721
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC4380717
ISSN:	0390-6078 1592-8721 1592-8721
DOI:	10.3324/haematol.2014.113886