Role of polymorphic sequences 5' to the G(gamma) gene and 5' to the beta gene on the homozygous beta thalassemic phenotype.

Sixty-seven homozygous male and female thalassemic patients with different phenotypes, aged between 8 and 33 years, were divided into three groups, according to the severity of their beta-thalassemia (thal) mutations. We investigated whether some co-inherited genetic factors could influence the phenotype. Patients with milder beta-thal defects, homozygotes or compound heterozygotes for the IVS-I-6 (T-->C) or -87 (C-->G) mutations had a milder disease. In addition, determination of the co-inheritance of the -158 (C-->T) G(gamma) polymorphism and the (AT)9T5 repeat motif in the region -540 to -525, 5' to the beta-globin gene, showed that in some patients with severe or mild/severe beta-thal mutations, linked to haplotype III, there was higher Hb F expression. We conclude that in homozygous beta-thal patients, the severity of the mutations is the most important factor influencing the phenotype, but some polymorphisms such as the -158 (C-->T) G(gamma) and (AT)9T5 repeat motif, increasing the Hb F expression and ameliorate the clinical course of the disease.