Genetic and non-genetic factors affecting hemoglobin A2 expression in a large cohort of Thai individuals: implication for population screening for thalassemia.

ABSTRACT

OBJECTIVE: Increased hemoglobin (Hb) A2 level is an important diagnostic marker for ß-thalassemia carrier screening. The level of Hb A2 is also useful for differentiating several thalassemia syndromes. We have examined data bases for reduced Hb A2 expression in a large cohort of Thai subjects. METHODS: A study was done on 1,498 subjects with non-thalassemia and various types of thalassemia and Hb variants to determine the effect of thalassemia genotypes and on 103 women of reproductive age to determine the effect of iron deficiency. Hb analysis was done using capillary electrophoresis, and thalassemia genotypes were defined by DNA analysis. Serum ferritin was measured using chemiluminescent microparticle immunoassay. RESULTS: Subjects were divided into 35 groups based on iron status, Hb, and DNA analysis. Decreased Hb A2 level was observed in those with Hb Q-Thailand, δ-hemoglobinopathies, δß0-thalassemia, Hb Lepore, iron deficiency, α-thalassemia, and especially Hb Constant Spring (Hb CS). While ß-thalassemia carriers with Hb H disease still had elevated Hb A2 levels, most of the ß-thalassemia carriers with Hb H-CS disease had Hb A2 less than 3.5% as a diagnostic cut-off. The lowest Hb A2 level was observed in those with Hb H-CS disease. CONCLUSION: Iron deficiency, Hb CS trait, homozygous Hb CS, and Hb H disease may reduce Hb A2 level, leading possibly to misdiagnosis of ß-thalassemia, especially in carriers with borderline Hb A2. Hb CS showed the strongest effect on Hb A2 expression. Understanding the basis for reduced Hb A2 expression may help reduce the diagnostic pitfalls of ß-thalassemia in the region.