title: A genetic score for the prediction of beta-thalassemia severity.
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.
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy fabdanjou@yahoo.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Danjou
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Francavilla
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Anni
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Satta
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Franca-Rosa
authors.initials: FR
authors.lastname: Demartis
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Perseu
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Manca
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Sollaino
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Manunza
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mereu
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marceddu
authors.affiliation: Laboratoire de Génétique, Hôpital Henri Mondor, Créteil, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Pissard
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Joly
authors.affiliation: French reference center for Thalassemia and Service d'Onco-Hématologie Pédiatrique, Assistance Publique Hôpitaux de Marseille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thuret
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Origa
authors.affiliation: Department of Applied Biomedical Science, Faculty of Health Sciences and Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
authors.forename: Joseph
authors.initials: J
authors.lastname: Borg
authors.affiliation: Ematologia - Centro della Microcitemia ed Anemie Congenite, Ospedale Galliera, Genova, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Forni
authors.affiliation: Università di Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Piga
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Maria Eliana
authors.initials: ME
authors.lastname: Lai
authors.affiliation: French reference center for Thalassemia and Department of Genetics, Assistance Publique Hopitaux de Marseille and Aix-Marseille University, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Moi
authors.affiliation: Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Italy Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Galanello
mesh_terms: D001803:Blood Transfusion; D021901:DNA, Intergenic; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D014644:Genetic Variation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000628:therapy
chemical_list: D021901:DNA, Intergenic; D055544:beta-Globins