Identifying genetic factors determining foetal haemoglobin levels in Sickle Cell Disease

Other investigators/ Supervisors:
Prof. SL Thein (Kings College, London)
Prof. S Menzel (Kings College, London)

Despite their apparent genetic simplicity, it has long been appreciated that both ß-thalassemia and sickle cell disease (SCD) display a remarkable diversity in the severity of their disease. High levels of HbF have been shown to have a beneficial effect in both of these disorders, although the mechanism for the ameliorating effect differs. The occurrence of some complications of SCD like osteonecrosis, acute chest syndrome, and painful episodes are reduced by increased concentrations of HbF, and HbF levels are inversely associated with mortality. However, HbF levels have been found to vary not only in sickle cell patients but also in normal individuals. It is now clear that common HbF variation is a quantitative genetic trait shaped by common polymorphisms. Twin studies have shown that HbF trait is highly heritable. Furthermore, data from linkage studies have recommended that both loci within the globin gene cluster may play a role in the regulation of HbF levels. Recent association studies have suggested that a variant between the HBS1L and c-MYB genes is implicated in the QTL for HbF at 6q23 as well as the BCL11A loci in chromosome 2. These three major loci are reported to contribute 20-50% of the trait variance in patients with SCD as well as healthy individuals. Although there have been many studies on the association of HbF levels with various loci in the human genome, few studies have been done in Africa, where up to 80% of global SCD population live. In Tanzania, SCD causes a significant burden to individuals, communities and health care systems having a high prevalence; high mortality and morbidity from chronic disability due to anaemia, painful crises and other events that result in considerable burden to the health system. It is thus worth understanding the genetic patterns in SCD patients in Tanzania and comparing them to other populations that have been studied as the relative frequency of complications may be different and better understanding may lead to affordable interventions with minimal side effects. Furthermore, since HbF is linked to severity of the disease, having genetic markers that can be used to predict HbF levels from early childhood would help to plan for better health care.

Current knowledge in genomics suggests that the heterogeneity in SCD is more likely due to several genetic factors with varying effects rather than from a single genetic factor. From the phenotypic information available from the cohort, we can group patients with low and high risk of severe disease. Using a combination of genotyping approaches, we will identify markers associated with protection or susceptibility. These variants would then be explored in detail in a larger patient data set, using a case - control approach. Note that due to the high genetic diversity in Africa, there is a need to determine sequence variation at population level; thus we will share knowledge and resources from networks such as MalariaGEN, for which MUHAS is a site. This approach and discovery of causal/protective variants will contribute to knowledge on disease mechanisms which will allow the development of prevention, diagnosis and treatment strategies. Furthermore, they will allow better characterisation of SCD patients as we will be integrating genotypic data to clinical laboratory and imaging data.