Dr. Thein’s research examines the genetic factors underlying the phenotypic variability of sickle cell disease and beta thalassemia disorders. Both of these conditions are caused by mutations affecting the beta globin gene.
A crucial difference between these conditions is that beta thalassemia results from a reduced number of red blood cells, while sickle cell disease results from abnormal "sickle" hemoglobin, or HbS, that makes red blood cells rigid and sickle-shaped, causing acute intermittent pain due to blockages of blood vessels and interruption of oxygen supply to vital organs. The rigid red blood cells are also very fragile and easily destroyed, causing a life-long anemia.
HbF is the blood component primarily responsible for fetal oxygen transport and is present in infants until they are about 6 months old. The persistence of HbF beyond infancy is highly variable. High levels of HbF minimize many complications of sickle cell disease and can increase life expectancy. Drug therapy can reactivate HbF production in both children and adults, reducing the severity of sickle cell and beta thalassemia symptoms.
By studying identical twins, who share very similar DNA, Dr. Thein’s lab has demonstrated that HbF levels are predominantly genetically controlled, and that almost 90 percent of the difference in HbF levels from person to person can be accounted for by differences in genetic background, both outside and within the environment of the beta globin gene. Through genetic studies, she has identified segments of DNA, called quantitative trait loci, on chromosome 11p (where the beta globin gene is located), chromosome 6q, and the BCL11A gene on chromosome 2p that are involved in stimulating HbF production in adults. These have now been associated with increased HbF in diverse populations, both with and without sickle cell disease or beta thalassemia and have a beneficial clinical effect. Although the quantitative trait loci account for up to 50% of the HbF difference, a substantial proportion of HbF variation remains unexplained. Further, individual differences in HbF and alpha thalassemia trait loci do not account for all the variation in clinical severity.
Dr. Thein and her research team now hope to identify and validate genetic and biomarkers that will allow early detection and monitoring of severe sickle cell complications, using new genome technologies and deep phenotyping. They plan to contribute to discovery and development of drugs designed for treatment of sickle cell disease, including those that promote HbF synthesis and inhibit HbS polymerisation. They specifically would like to explore targeting the 6q HBS1L-MYB intergenic enhancers as a genetic therapeutic approach for reactivating fetal hemoglobin. By gaining a deeper understanding of the pathophysiology of acute sickle pain, they hope to develop treatments to reduce severity and length of acute vaso-occlusive crises.
Identification of the HbF loci has invigorated interest in re-activating the production of fetal hemoglobin in the treatment of sickle cell disease and beta thalassemia. Through her research, Dr. Thein hopes to eventually delineate the genetic architecture of fetal hemoglobin control in adults and identify the loci and sequence variants that account for disease variance among individual adults. This work will have implications for novel therapeutic options, more accurately informed genetic counseling, and improved predictive diagnosis of disease severity in sickle cell and beta thalassemias.