Sickle Cell Disease Study

Sickle-cell disease is a condition that affects approximately 275,000 babies in Africa each year and, if untreated, can prove fatal.

Sickle-cell disease (SCD) refers to a group of recessive genetic conditions that are expressed when both versions of a person’s β-globin gene in haemoglobin have mutations (either HbS or HbC). It is characterized by red blood cells that assume an abnormal, rigid, sickle shape causing them to have decreased flexibility. The abnormal red cells break down, causing anaemia, and obstruct blood vessels, leading to recurrent episodes of severe pain, multi-organ ischemic damage and shortened life-span. If untreated the mortality is high, 50-90 per cent by five years of age. Symptomatic treatments exist for SCD, but there is currently no cure, and the disease has been declared a public healthy priority by the World Health Organization.

Each year, about 275,000 children are born in Africa with SCD (>75 per cent of the global burden) and in sub-Saharan Africa approximately one-third of the population carry a single variant of the sickle cell gene, known as sickle-cell trait. The reason for the high prevalence of the disease in Africa is that a single copy of the haemoglobin mutation is protective against the invasion of the red blood cells by Plasmodium falciparum, the parasite which causes the most fatal form of malaria. Children who carry one copy of the most common sickle cell haemoglobin variant (HbAS) have a ten-fold reduced risk of fatal forms of malaria compared to those who do not carry the variant.

[CDC/Janice Haney Carr]

Julie Makani. KEMRI-Wellcome Trust Research Programme.

Julie Makani. KEMRI-Wellcome Trust Research Programme. [Genome Research Limited]

Our Project

Sickle cell disease can result from having either two copies of the β-globin HbS mutation (SCD-SS) or a copy of of HbS and a copy of HbC (SCD-SC). In addition, it is also found in combination with β-thalassaemia (which causes a reduced rate of synthesis of β-globin), producing a spectrum of sickle-cell/ β-thalassaemia (SCD-βthal) conditions. The clinical course of patients with sickle cell anaemia is highly variable. Fetal haemoglobin (HbF) concentration (itself a quantitative trait that is influenced by genetic factors) and the presence of β-thalassemia are established factors that influence the long-term clinical diversity of the disease, but other modifier genes and additional environmental factors (nutritional status, access to healthcare and presence of infections) are likely to also contribute.

In collaboration with Julie Makani in Dar es Salaam, Tanzania, we are conducting a genome-wide association study (GWAS) to examine genetic factors affecting the clinical spectrum of SCD in a large cohort of individuals homozygous for the HbS mutation. We are assessing both quantitative traits and clinical haematological and neurological disorders associated with SCD in order to better understand the molecular, genetic and environmental mechanisms determining disease course and severity in Africa. This project will also provide an excellent opportunity to better understand the challenges to genetic studies in Africa posed by high levels of diversity and admixture.

In the future, we hope to extend this study to other regions of East Africa by collaborating with other partners in the region, and that this work might eventually inform the development and application of SCD interventions.

Partners

* quick link - http://q.sanger.ac.uk/2qocp8xg