Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion

• Published in: Haematologica (Roma) Vol. 97; no. 7; pp. 989 - 993
• Main Authors: DANJOU, Fabrice, ANNI, Franco, PERSEU, Lucia, SATTA, Stefania, DESSI, Carlo, LAI, Maria Eliana, FORTINA, Paolo, DEVOTO, Marcella, GALANELLO, Renzo
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01-07-2012
• Subjects: Adolescent; Adult; Age Factors; alpha-Globins - genetics; Anemias. Hemoglobinopathies; beta-Globins - genetics; beta-Thalassemia - genetics; beta-Thalassemia - mortality; beta-Thalassemia - pathology; Biological and medical sciences; Blood Transfusion; Carrier Proteins - genetics; Cohort Studies; Diseases of red blood cells; DNA Fingerprinting; DNA, Intergenic - genetics; Female; Fetal Hemoglobin - genetics; Genetic Loci; Genetic Markers; Hematologic and hematopoietic diseases; Humans; Male; Medical sciences; Middle Aged; Nuclear Proteins - genetics; Original and Brief Reports; Polymorphism, Single Nucleotide; Proportional Hazards Models; Severity of Illness Index; Survival Analysis; thalassemia major; Hemoglobinopathy; Transfusion; Hematology; Hemopathy; beta-thalassemia; genetic modifiers; thalassemia intermedia; Genetic disease; Fetal hemoglobin; Hemolytic anemia; β-Thalassemia; Genetics; Age
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2011.053504

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.
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.
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.
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.