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

Abstract

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 <i>MAP3K5</i>, <i>ASS1</i>, <i>NOS2A</i>, <i>TOX</i>, <i>PDE7B</i>, <i>NOS1, FLT1</i> and <i>ARG2</i>, 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 (<i>HBB</i>: 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 <i>MAP3K5</i>, <i>NOS2A</i> and <i>ARG2</i> gene are associated with HU therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that <i>FLT1</i> and <i>ARG2</i> genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that <i>MAP3K5</i>, <i>NOS2A</i>, <i>ARG2 and FLT1</i> 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.