Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in beta-Thalassemia Intermedia: A Validation Cohort Study

摘要

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 beta-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 P 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 p-thalassemia patients (P-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDTl 42 Hb S {HBB: c.20A>T)-p-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 MAP3KS, NOS2A and ARG2 gene are associated with HU therapy efficacy in Hb S-p-thal compound heterozygotes. We have also shown that FLT1 and ARC2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3KS, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-p-thal compound heterozygotes and also to describe disease severity in patients with p type hemoglobinopathies.