Beta-thalassaemia-87 C > G: relationship of the Hb F modulation and polymorphisms in compound heterozygous patients

A clinical, haematological, biochemical and molecular study was carried out in 17 patients affected with thalassaemia intermedia, who were compound heterozygotes for the beta-thalassaemia mutation beta-87 C-->G to determine the genetic basis of their clinical heterogeneity. The beta-87 was found associated with haplotype VIII (beta-87/VIII) or V (beta-87/V). The 10 patients with the beta-87/VIII showed milder clinical conditions, with significantly higher levels of haemoglobin (Hb) (9.8 +/- 1.1 g/dl vs. 8.5 +/- 1.3 g/dl) and fetal haemoglobin (Hb F) (6.2 +/- 1.5 g/dl vs. 2.6 +/- 1.5 g/dl; P = 0.0034) and higher synthesis of (G)gamma ((G)gamma/(Total)gamma 69.4 +/- 2.6% vs. 42.8 +/- 16.2%; P = 0.0042) than the seven patients with the beta-87/V. The beta-87/VIII showed a configuration of rare polymorphisms in the 5' sub-haplotype, which have been reported to exert an increasing effect on Hb F. They were "T"-158 (G)gamma-globin gene, T-A-G in pre-(G)gamma framework, (TG)(11)(CG)(3) in the (G)gamma-IVS2, (AT)(9)N(12)(AT)(10) in LCR-HS2; in contrast, the haplotype V had, respectively, "C", T-G-A (TG)(19)(CG)(2)CACG in the (G)gamma-IVS2, and (AT)(10)N(12)(AT)(11). In all patients the beta-87 was associated with the (AT)(9)T(5) motif 5' beta-globin gene with increased affinity for the BP-1 protein, and with the (TG)(13) in the (A)gamma-IVS2. The high increase of the Hb F, mostly of the (G)gamma-type, strongly suggests the hypothesis that the 'T'-158 (G)gamma plays a principal role and that the other polymorphisms could exert a cooperative role in the modulation of Hb F in patients with erythropoietic stress.