Genetic Modifiers of Fetal Haemoglobin (HbF) and Phenotypic Severity in β-Thalassemia Patients

S A A Razak; N A A Murad; F Masra; D L S Chong; N Abdullah; N Jalil; H Alauddin; R Z A R Sabudin; A Ithnin; L C Khai; N A Aziz; Z Muda; H Ibrahim; Z A Latiff

doi:10.2174/1566524018666181004121604

Genetic Modifiers of Fetal Haemoglobin (HbF) and Phenotypic Severity in β-Thalassemia Patients

Curr Mol Med. 2018;18(5):295-305. doi: 10.2174/1566524018666181004121604.

Authors

S A A Razak¹, N A A Murad¹, F Masra², D L S Chong², N Abdullah¹, N Jalil³, H Alauddin³, R Z A R Sabudin³, A Ithnin³, L C Khai², N A Aziz⁴, Z Muda⁵, H Ibrahim⁵, Z A Latiff²

Affiliations

¹ UKM Medical Molecular Biology Institute, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
² Department of Paediatrics, Faculty of Medicine, University Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
³ Department of Pathology, Faculty of Medicine, University Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
⁴ Institute for Medical Research (IMR), Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
⁵ Institute of Paediatrics, Hospital Kuala Lumpur, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.

PMID: 30289070
DOI: 10.2174/1566524018666181004121604

Abstract

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 severity.

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.

Keywords: HbF modifiers; genotype-phenotype association; mutation; polymorphisms; severity of disease; β-thalassemia..

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Child
Female
Fetal Hemoglobin / genetics*
GTP-Binding Proteins / genetics*
Humans
Male
Multigene Family*
Polymorphism, Single Nucleotide*
Proto-Oncogene Proteins c-myb / genetics*
beta-Thalassemia / genetics*

Substances

MYB protein, human
Proto-Oncogene Proteins c-myb
Fetal Hemoglobin
GTP-Binding Proteins
HBS1L protein, human