Background: The phenotypic severity of β-thalassemia is highly modulated
by three genetic modifiers: β-globin (HBB) mutations, co-inheritance of α-thalassemia
and polymorphisms in the genes associated with fetal haemoglobin (HbF) production.
This study was aimed to evaluate the effect of HbF related polymorphisms mainly in the
HBB cluster, BCL11A (B-cell CLL/lymphoma 11A) and HBS1L-MYB (HBS1-like
translational GTPase-MYB protooncogene, transcription factor) with regards to clinical
Methods: A total of 149 patients were included in the study. HBA and HBB mutations
were characterised using multiplex PCR, Sanger sequencing and multiplex ligationdependent
probe amplification. In addition, 35 HbF polymorphisms were genotyped
using mass spectrometry and PCR-restriction fragment length polymorphism (PCRRFLP).
The genotype-phenotype association was analysed using SPSS version 22.
Results: Twenty-one HBB mutations were identified in the study population. Patients
with HBB mutations had heterogeneous phenotypic severity due to the presence of
other secondary modifiers. Co-inheritance of α-thalassemia (n = 12) alleviated disease
severity of β-thalassemia. In addition, three polymorphisms (HBS1LMYB, rs4895441 [P
= 0.008, odds ratio (OR) = 0.38 (0.18, 0.78)], rs9376092 [P = 0.030, OR = 0.36 (0.14,
0.90)]; and olfactory receptor [OR51B2] rs6578605 [P = 0.018, OR = 0.52 (0.31, 0.89)])
were associated with phenotypic severity. Secondary analysis of the association
between single-nucleotide polymorphisms with HbF levels revealed three nominally
significant SNPs: rs6934903, rs9376095 and rs9494149 in HBS1L-MYB.
Conclusion: This study revealed 3 types of HbF polymorphisms that play an important
role in ameliorating disease severity of β-thalassemia patients which may be useful as a
predictive marker in clinical management.