Format

Send to

Choose Destination
Haematologica. 2012 Jul;97(7):989-93. doi: 10.3324/haematol.2011.053504. Epub 2012 Jan 22.

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

Author information

1
Clinica Pediatrica 2a, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Ospedale Regionale Microcitemie ASL8, Cagliari, Italy.

Abstract

BACKGROUND:

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.

DESIGN AND METHODS:

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.

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 α-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 β(0)-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with β-thalassemia.

PMID:
22271886
PMCID:
PMC3396667
DOI:
10.3324/haematol.2011.053504
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center