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HBB genotype in TDT in Cyprus
severity-alleviating factors, such as α0 deletions and minor allele of the XmnI polymorphism, is low in this population and is unlikely to have affected the overall analysis of sur- vival. In contrast, HBB genotype appears to be a significant determinant of severity, a finding confirmed in a study of likelihood of initiation of transfusion in patients with β-tha- lassemia, in whom transfusion was 30 times more likely in those with a severe genotype than in those with a mild genotype.15,16 The effect of genotype on survival could potentially be biased due to deaths of patients with severe genotypes at an earlier age and exclusion of patients who died early in the follow-up, before genotyping was intro- duced in Cyprus. Nevertheless, this is unlikely to have a major influence on our conclusions, because there was no significant difference between genotype frequencies and age at death in patients with available genotypes, while the year of birth was used in a multivariate survival analysis (data not shown) without materially changing the significant effect of genotype on survival.
Survival in TDT is associated with a variety of risk fac- tors, not all of which are quantifiable, and these risk fac- tors are likely to differ according to the cause of mortality. The cause of mortality appears to be changing from car- diac iron overload to other etiologies more closely associ- ated with the long-term effects of inadequate suppression of the underlying thalassemia phenotype. Our results suggest that HBB genotype could affect mortality through its causative effect on disease phenotype, which is now more apparent because of the reduction of cardiac deaths. The analysis of transfusion data shows that patients with mild genotypes are beginning transfusion significantly later in life and require less blood. However, once started on transfusion, there is no difference in pre-transfusion hemoglobin level between the genotypes, indicating that lower volumes of blood are required to suppress ineffec- tive erythropoiesis in the group with mild genotypes. These observations in this study suggest that the delay in starting transfusion, along with the long-term transfusion strategy, are likely to have a negative impact on the sur- vival of patients with mild genotypes. Notably, current treatment guidelines for TDT recommend that the deci- sion about starting transfusion is based on clinical assess- ment. Our results suggest that determining the HBB geno-
type and using this information to aid in decision-making could improve long-term outcomes.
The effect of genotype on mortality could be examined in other previously described thalassemia cohorts2,6,7 and in combined datasets, thus allowing the study of a more diverse spectrum of genotypes. This is a future direction of our work. If confirmed, the effect of genotype could have significant implications for the management of TDT. Firstly, it would provide evidence that patients diag- nosed with β-thalassemia should initiate regular transfu- sion early, using a transfusion regimen which effectively suppresses erythropoiesis, to avoid long-term complica- tions of uncontrolled anemia and marrow expansion. Secondly, it would contribute to the decision of whether to institute emerging strategies for treating TDT including enhancement of endogenous erythropoiesis,34 as well as lentiviral and gene editing strategies,35,36 both of which appear to be more effective in patients with milder geno- types and higher residual globin chain production.
Disclosures
PT was principal investigator in a phase III study of luspater- cept, a product of Celgene Corporation; he has received research funding from and participated in advisory boards for Bluebird Bio, Inc; and has participated in advisory boards for Novartis and Apopharma.
Contributions
PK, MK and PT designed the study protocol, and wrote and edited the manuscript; SC, MH, MS and AK managed the patients according to national and international guidelines and col- lected clinical data; PK and MK performed the DNA studies; PK, KM and PT performed the statistical analysis.
Acknowledgments
We wish to thank the Cypriot patients and families attending the Greek Cypriot thalassemia clinics and the staff in these centers who have provided dedicated, long-term care over the study period.
Funding
This work was partially funded by the THALAMOSS project (FP7-HEALTH-2012-INNOVATION-1: grant agreement 306201).
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