Iron metabolism and genetic modifiers in thalassemia and sickle cell anemia

Iron metabolism plays a crucial role in the management of hemoglobinopathies, particularly in conditions such as β-thalassemia and sickle cell disease (SCD). This paper reviews briefly the present knowledge of iron overload in patients with transfusion-dependent thalassemia (TDT), non-transfusion-dependent thalassemia (NTDT), and SCD, highlighting the distinct paths leading to iron accumulation in each condition. The primary focus of this review is on the role of known genetic modifiers that influence iron metabolism and the variability in iron overload presentation among those patients. Genetic pathogenic variants in genes such as HFE, HRFE, HAMP, TFR2, SLC40A1, and others significantly impact iron regulation. These modifiers can exacerbate or ameliorate iron overload. Better understanding the role of those (and other) genetic factors is important for explaining the diverse disease severity and differences in the mechanism and clinical presentation of iron overload in these patients. The ongoing the International Hemoglobinopathy Research Network (INHERENT) study aims to further elucidate the influence of these (and other) unknown genetic modifiers through a comprehensive genome-wide association study. This project can potentially lead to novel therapeutic interventions for managing iron homeostasis in patients with hemoglobinopathies.