Variation and heritability of Hb F and F-cells among β-thalassemia heterozygotes in Hong Kong

Enhanced fetal hemoglobin (Hb F) production can partially compensate for the lack of adult hemoglobin (Hb A) in patients with beta-thalassemia major or intermedia, and ameliorate the clinical severity of these diseases. To further elucidate factors governing Hb F levels, we evaluated demographic, clinical, laboratory, and genetic characteristics in 241 unrelated adult beta-thalassemia carriers in Hong Kong. They had wide variations in Hb F and F-cell numbers skewing toward higher levels. Individuals who coinherited the Xmn I T-allele in the ay-globin gene promoter had higher Hb F and more F-cells compared with those lacking the Xmn I T-allele. However, both groups exhibited a similarly wide spread of Hb F and F-cells. The correlation of Hb F and F-cells corresponded well to both linear and exponential models, suggesting multiple mechanisms for Hb F augmentation. The heritabilities of Hb F and F-cells were calculated in 66 families (111 parents who were beta-thalassemia carriers and 82 asymptomatic offspring) to be 0.7 to 0.9. The Xmn I polymorphism accounted for 9% of the Hb F and 13% of the F-cell heritabilities. These results suggest that these family members are well suited for genome wide association studies that will identify genetic loci regulating Hb F production, and likely novel pharmacological targets for reactivating Hb F production in adults.