Haemoglobin switching modulator SNPs rs5006884 is associated with increased HbA2 in β-thalassaemia carriers

Abstract

Introduction: Haemoglobin A 2 (HbA 2), the tetramer of αand δ-globin chains, is used as a diagnostic biomarker for β-thalassaemia carriers. The HbA 2 levels are regulated by the presence of HPFH, δ-thalassaemia, HbA 1/2 gene triplication, and variants of KLF1, β-globin gene, and HbF regulating QTLs. Saudi Arabia has a high incidence of borderline HbA 2 levels, thereby making it difficult to classify the haemoglobinopathies. This study aims to investigate the association of known HbF enhancer QTL gene SNPs with HbA 2 levels Material and methods: 14 Specific SNPs in BCL11A, HMIP, OR51B6, HBBP1, and HBG2 loci were genotyped in 164 Saudi β-thalassaemia carriers by TaqMan assay to validate their role as regulators of HbA 2 levels. HbA2 levels were determined using the Variant II β-Thalassemia Short Program Recorder kit. The non-random association of these SNPs was tested using HaploView software. Protein interaction was assessed using 3D structure modelling for OR51B6 (rs5006884), comparative energy minimisation, and root-mean-square deviation (RMSD) prediction. Results: Elevated HbA 2 levels were associated with SNPs in HBBP1, OR51B6, and TCT haplotype from HBG2 promoter region. The bioinformatics modelling and prediction revealed that the exonic rs5006884 had RMSD value deviations and significantly varied binding energy minimisation. α-globin variations were found in 57.92% of individuals but were not associated with elevated HbA 2. Conclusions: The haemoglobin switching modulators rs2071348, rs7482144, and rs5006884 are involved in regulation of HbA 2 level with rs5006884 influencing the tetramer formation. Screening for haemoglobinopathies should take these SNPs into consideration, specifically in borderline HbA 2 cases. Assiduous analysis of rs5006884 as HbA 2 modulator for amelioration of disease severity is recommended.

Molecular basis of a high Hb A2/Hb Fβ-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction withα-globin gene triplication

“…It has been shown that the four bp deletion (-AGCA) at −225 to −222 of the A γ -globin gene was associated with reduced A γ -globin chain and elevation of G γ chain with slightly increased Hb F level in β -thalassemia subjects ( Manca et al, 1991 ; Ugrin et al, 2016 ). The rs5006884 (C>T) on OR51B6 gene located upstream of β -globin gene cluster might intervene in the tetramer formation of α -globin chain with β - and δ -globin chains and regulated Hb A 2 level in β -thalassemia carriers ( Cyrus et al, 2019 ). The −158 G γ - Xmn I polymorphism is associated with high Hb F expression in β -hemoglobinopathies during erythropoietic stress ( Thein, 2017 ).…”

Clinical application of targeted long read sequencing in prenatal beta‐thalassemia testing and genetic counseling

“…HbA2 levels in beta thalassemia carriers can be lowered by certain modifiers, including iron deficiency and co‐inheritance of beta thalassemia with alpha or delta thalassemia (Colaco & Nadkarni, 2021). Conversely, in recent years, β‐globin gene expression modifier variants in KLF1 , HBG2, HBBP1, OR51B6 have been reported to be associated with elevated HbA2 levels (Cyrus et al, 2021).…”

“…HbA2 levels, however, are also known to be subject to modifiers such as iron deficiency and other genetic factors (Colaco & Nadkarni, 2021; Cyrus et al, 2021). Approximately 0.9% of ethnic Chinese individuals who display elevated HbA2 levels do not carry any identifiable disease‐associated variant on HBB genetic analysis (Jiang et al, 2018).…”