Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human β-
globin cluster have been shown to be significantly associated with Hb F increase, in relation to
hydroxyurea (HU)
therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as MAP3K5, ASS1, NOS2A, TOX, PDE7B, NOS1, FLT1 and ARG2, previously shown to modulate
fetal hemoglobin (Hb F) levels in patients with β type
hemoglobinopathies and reflecting disease severity and response to HU
therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 β-
thalassemia patients (β-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (HBB: c.20A>T)-β-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the MAP3K5, NOS2A and ARG2 gene are associated with HU
therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that FLT1 and ARG2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3K5, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic
biomarkers to predict HU
therapy efficacy in Hb S-β-thal compound heterozygotes and also to describe disease severity in patients with β type
hemoglobinopathies.