Interplay between α‐thalassemia and β‐hemoglobinopathies: Translating genotype–phenotype relationships into therapies

Abstract α‐Thalassemia represents one of the most important genetic modulators of β‐hemoglobinopathies. During this last decade, the ongoing interest in characterizing genotype–phenotype relationships has yielded incredible insights into α‐globin gene regulation and its impact on β‐hemoglobinopathies. In this review, we provide a holistic update on α‐globin gene expression stemming from DNA to RNA to protein, as well as epigenetic mechanisms that can impact gene expression and potentially influence phenotypic outcomes. Here, we highlight defined α‐globin targeted strategies and rationalize the use of distinct molecular targets based on the restoration of balanced α/β‐like globin chain synthesis. Considering the therapies that either increase β‐globin synthesis or reactivate γ‐globin gene expression, the modulation of α‐globin chains as a disease modifier for β‐hemoglobinopathies still remains largely uncharted in clinical studies.