Introduction: Elevated HbA₂ (hemoglobin A₂) level is considered the most reliable hematological parameter for the detection of β-thalassemia carriers. However, some carriers are difficult to recognize because the level of HbA₂ is not in the distinctive carrier range, i.e. 4.0–6.0%; instead, some carriers have HbA₂ levels between normal and carrier levels, i.e. borderline HbA₂ (HbA₂ = 3.1–3.9%). Studies have shown that variations in the erythroid Krüppel-like factor (KLF1) gene lead to borderline HbA₂ in β-thalassemia carriers from various populations. The incidence of borderline HbA₂ in Saudis is high.
Material and methods: To confirm the influence of variations in KLF1, HBA1, HBA₂ and HBB genes for the reduction of the level of HbA₂ in Saudi β-thalassemia carriers, we performed a direct sequence analysis of KLF1, HBA1, HBA₂ and HBB genes from 212 healthy Saudis (88 subjects: HbA₂ < 3; 72 subjects: HbA₂ = 3.1 to 3.9; 52 subjects HbA₂ > 4.3).
Results: The presence of the borderline HbA₂ level is not specific to any type of β-thalassemia variation or β⁺-thalassemia variations in Saudis. Two exonic (c.304T>C and c.544T>C) and two 3 untranslated region (3UTR) (c.*296G>A and c.*277C>G) variations have been identified in the KLF1 gene for the first time from an Arab population. None of these four variations in KLF1 genes are significantly associated with the Saudis with borderline HbA₂. α Globin genotype, –α₂^3.7/α₁α₂, is found to be the most frequent (55.55%) among healthy Saudis with borderline HbA₂ compared with the other groups (HbA₂ < 3 = 20.45%; HbA₂ > 4.3 = 13.51%).
Conclusions: Further studies are necessary to determine the influence of other factors on the presence of borderline HbA₂ in 41.67% of Saudis.