Genetic modifiers of fetal haemoglobin (HbF) and phenotypic severity in β-thalassemia patients

S. A.A. Razak, Nor Azian Abdul Murad, F. Masra, D. L.S. Chong, Noraidatulakma Abdullah @ Muda, N. Jalil, Hafiza Alauddin, Raja Zahratul Azma Raja Sabudin, Azlin Ithnin, L. C. Khai, N. A. Aziz, Z. Muda, H. Ibrahim, Zarina Abdul Latiff

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 ligation-dependent probe amplification. In addition, 35 HbF polymorphisms were genotyped using mass spectrometry and PCR-restriction fragment length polymorphism (PCR-RFLP). 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.

Original languageEnglish
Pages (from-to)295-305
Number of pages11
JournalCurrent Molecular Medicine
Volume18
Issue number5
DOIs
Publication statusPublished - 1 Jan 2018

Fingerprint

Fetal Hemoglobin
Thalassemia
Polymorphism
Mutation
Multiplex Polymerase Chain Reaction
Odds Ratio
Single Nucleotide Polymorphism
Odorant Receptors
Globins
GTP Phosphohydrolases
Genetic Association Studies
B-Cell Lymphoma
Restriction Fragment Length Polymorphisms
Mass Spectrometry
Transcription Factors
Biomarkers
Mass spectrometry
Amplification
Polymerase Chain Reaction
Nucleotides

Keywords

  • Genotype-phenotype association
  • HbF modifiers
  • Mutation
  • Polymorphisms
  • Severity of disease
  • β-thalassemia

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology

Cite this

Genetic modifiers of fetal haemoglobin (HbF) and phenotypic severity in β-thalassemia patients. / Razak, S. A.A.; Abdul Murad, Nor Azian; Masra, F.; Chong, D. L.S.; Abdullah @ Muda, Noraidatulakma; Jalil, N.; Alauddin, Hafiza; Raja Sabudin, Raja Zahratul Azma; Ithnin, Azlin; Khai, L. C.; Aziz, N. A.; Muda, Z.; Ibrahim, H.; Abdul Latiff, Zarina.

In: Current Molecular Medicine, Vol. 18, No. 5, 01.01.2018, p. 295-305.

Research output: Contribution to journalArticle

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AU - Razak, S. A.A.

AU - Abdul Murad, Nor Azian

AU - Masra, F.

AU - Chong, D. L.S.

AU - Abdullah @ Muda, Noraidatulakma

AU - Jalil, N.

AU - Alauddin, Hafiza

AU - Raja Sabudin, Raja Zahratul Azma

AU - Ithnin, Azlin

AU - Khai, L. C.

AU - Aziz, N. A.

AU - Muda, Z.

AU - Ibrahim, H.

AU - Abdul Latiff, Zarina

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 ligation-dependent probe amplification. In addition, 35 HbF polymorphisms were genotyped using mass spectrometry and PCR-restriction fragment length polymorphism (PCR-RFLP). 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.

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KW - Polymorphisms

KW - Severity of disease

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