Blood disorders such as β-thalassemia and sickle-cell anaemia arise due to mutations in the genes encoding the β-globin subunits of haemoglobin. Haemoglobin is a tetrameric heterodimer composed of two α-like and β-like subunits present in red blood cells that is essential for carrying oxygen around the body. To cater for varying oxygen demands during development, the composition of haemoglobin changes in a tightly-regulated process known as globin switching. This involves two switches in the composition of β-globin, first from embryonic-to-foetal globin during gestation, and secondly from foetal-to-adult after birth. Due to compelling evidence suggesting that increased foetal-globin can compensate for loss of functional adult-globin, studies have aimed to uncover the mechanisms behind globin switching as a means to ‘reawaken’ the foetal genes therapeutically.

Healthy individuals with the 5’HS4-LCR A>G polymorphism in the locus control region of the β‑globin locus have higher levels of foetal-haemoglobin than individuals without the polymorphism. Furthermore, patients who have the A>G polymorphism who are suffering from β-thalassemia show reduced disease severity. Here we present research aiming to uncover the underlying molecular mechanism behind this phenotype. Future work will involve engineering the polymorphism into erythroid progenitor cell lines by CRISPR to investigate the effect of the polymorphism on globin expression, specifically in foetal-globin production. This will involve analysis of globin expression at the mRNA level by RT-PCR and at the protein level by flow cytometry. We aim to utilise understanding of the genetic variants of the β-globin locus to aid in informing novel therapeutic approaches to the treatment of blood disorders such as β‑thalassemia and sickle-cell anaemia.