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

Background The clinical and hematologic features of beta-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 alpha-globin and gamma-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of beta-thalassemia as assessed by the patients' age at first transfusion. Design and Methods We studied the effect of seven loci in a cohort of 316 Sardinian patients with beta(0)-thalassemia. In addition to characterizing the beta-globin gene mutations, alpha-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. Results 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 a-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population. Conclusions 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 beta(0)-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with beta-thalassemia.