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

ABSTRACT: BACKGROUND: The clinical and hematologic features of ?-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 ?-globin and ?-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of ?-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 ?(0)-thalassemia. In addition to characterizing the ?-globin gene mutations, ?-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 ?-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 ?(0)-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with ?-thalassemia.

SUBMITTER: Danjou F

PROVIDER: S-EPMC3396667 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Danjou Fabrice F Anni Franco F Perseu Lucia L Satta Stefania S Dessì Carlo C Lai Maria Eliana ME Fortina Paolo P Devoto Marcella M Galanello Renzo R

Haematologica 20120122 7

<h4>Background</h4>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.<h4>Design and methods</h4>W ...[more]

PMID: 22271886

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Project description:Background/aimsTransfusion dependent subjects are at a great risk of viral hepatitis infection. We aimed to evaluate the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among transfusion-dependent patients in Taiwan.MethodsA total of 140 patients (67 thalassemic patients, 70 hemophilic patients, two patients with hereditary spherocytosis and one patient with von Willebrand disease) were prospectively enrolled to evaluate the prevalence and factors associated with viral hepatitis and spontaneous HCV clearance. All patients were tested for HBV and HCV serology and virology. Two consecutive serum samples, at least 1 year apart, were collected to clarify HCV seroclearance.ResultsThe seropositivity rate of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and both HBsAg/anti-HCV were 6.4%, 45.7% and 5%, respectively. Logistic regression analysis of factors associated with anti-HCV seropositivity included age (odds ratio/95% confidence interval [OR/CI]: 1.12/1.07-1.18, P<0.001), serum alanine aminotransferase (ALT) (OR/CI: 1.04/1.02-1.06, P<0.001) and platelet counts (OR/CI: 0.995/0.991-0.998, P = 0.002). Age was the only factor independently associated with HBsAg seropositivity (OR/CI: 1.08/1.02-1.14.4, P = 0.007). Compared to patients born before 1992, the seroprevalence of HCV among thalassemic patients decreased dramatically in those born after 1992 (46.0% vs. 11.8%, p = 0.012). The seroprevalence of HCV among hemophilic patients also decreased significantly when comparing patients born before 1987 to those born after 1987 (79.5% vs. 11.5%, p<0.001). Similarly, the seroprevalence of HBV decreased significantly in the post-vaccination cohort compared to its counterpart (13.1%, vs. 1.3%, p = 0.005). The spontaneous clearance of HCV was observed in 25.4% (15/59) of patients, and ALT was the only factor associated with it (OR/CI 0.98/0.96-1.00, P = 0.02).ConclusionsBoth HBV and HCV infections are prevalent among transfusion-dependent thalassemic and hemophilic patients in Taiwan. Nevertheless, seroprevalence decreased significantly and dramatically for HCV after universal blood screening and for HBV after implementation of a universal mass vaccination program.

Dataset Information

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

Publications

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

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