Combined effect of two different polymorphic sequences within the β globin gene cluster on the level of HbF

β thalassemia and Hb Lepore heterozygotes included in this study exhibit fetal hemoglobin levels varying from trace quantities to 14% (1.74 g/dl) of total hemoglobin in the adult. In this work, we have examined the correlation of DNA sequence polymorphisms with the observed HbF level. The analysis of polymorphic markers within the β globin cluster in 39 individuals heterozygous for β thalassemia or Hb Lepore confirms the previous findings for homozygous β thalassemia: the presence of both an (AT)9 T5 sequence configuration at position −540 of the β globin gene and a (C T) variation at −158 of the Gγ globin gene is associated with elevated expression of HbF. However, at least one defective β globin gene is required to reveal this association. The best evidence is from the study of individuals heterozygous for Hb Lepore with various levels of HbF. In these individuals it was possible to explore the effect of a single (AT)x Ty motif (the other being absent from the rearranged Lepore chromosome) on HbF expression. The presence of the (AT)9 T5 configuration increases HbF level from a median of 0.515 g/dl observed in (AT)7 T7 subjects, to 1.39 g/dl. We confirm the existence of linkage disequilibrium between the (C T) variation at −158 of Gγ gene and the (TG)13 configuration at the second intervening sequence (IVS-2) of Aγ gene and identify two new polymorphisms in this region: (TG)7 (CG)5 (TG)8 linked to haplotype V and (TG)8 (CG)5 (TG)10 linked to haplotype II. This study suggests that two distinct regions of the β cluster, whether in cis or in trans to each other, can interact to enhance HbF expression when a β thalassemic determinant is present in heterozigosity. Am. J. Hematol. 57:269–276, 1998. © 1998 Wiley-Liss, Inc.