Genetic Variants in HBS1L-MYB rs9399137 and rs11759553 Associated with Elevated HbF Levels Among Filipino β°-deletion Carriers
Abstract
In Malaysia, Sabah population constitutes the most number of β-thalassaemia cases ranging from asymptomatic to transfusion dependent. Filipino β°-deletion has been reported as the predominant mutation in Sabah [1]. Despite having the same primary mutation, co-inheritance of genetic variants at HbF quantitative trait loci of HBS1L-MYB intergenic region may cause variability in clinical features by affecting the haemoglobin (Hb) subtypes level, especially HbF. Study suggested that MYB would activate γ-globin repressor gene directly and subsequently initiate the molecular HbF repression mechanisms. Polymorphisms within HBS1L-MYB intergenic region would inhibit binding of transcription factor on MYB and leading to elevation of HbF levels [2]. This can act as an ameliorating factor in the clinical presentation of β-thalassaemia patients [3]. This study aimed to elucidate the association of Hb subtypes levels with three HBS1L-MYB variants among 134 Filipino β°-deletion carriers. PCR-RFLP analysis was done for HBSIL-MYB rs4895441 (A→G) while tetra-primers ARMS PCR analysis was done for HBSIL-MYB rs9399137 (T→C) and rs11759553 (A→T) (Fig.1).Â
Through the genotyping analysis, two HBS1L-MYB variants (rs9399137, MAF = 0.18 and rs11759553, MAF = 0.190) were found with significant minor allele frequency (MAF) which is greater than .05. HBS1L-MYB rs4895441 showed no influential effect on Hb subtypes level. However, rs9399137 and rs11759553 showed significant different in HbF level. HbF level was elevated when Filipino β°-deletion carriers co-inherited with HBS1L-MYB rs9399137 or rs11759553 (Fig.2).Â
In conclusion, HBS1L-MYB rs9399137 and rs11759553 are significantly in elevating HbF levels which are not seen in rs4895441, making it a potent therapeutic target for gene therapy. The significant difference in Hb subtypes levels across the genotype variants had suggested the importance to include the detection of HBS1L-MYB rs9399137 and rs11759553 among Filipino β°-deletion patients in order to provide proper patient management.Â
References
Teh, L. K., et al., Molecular basis of transfusion dependent beta-thalassemia major patients in Sabah. Journal of Human Genetics. 2014. 59: p. 119-123.
Stadhouders, R., et al., HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. The Journal of Clinical Investigation, 2014.124(4): p. 1699-1710.
Cyrus, C., et al., Existence of HbF enhancer haplotypes at HBS1L-MYB intergenic region in transfusion-dependent Saudi β-thalassemia patients. BioMed Research International, 2017. p. 1-7.
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