A study published in Clinical and Translational Medicine, has assessed whole-exome sequencing data from sickle cell anaemia patients to identify contributors to variability in clinical expression.
Sickle cell disease (SCD) is a group of blood disorders caused by mutations in the HBB gene. These mutations prompt polymerisation of haemoglobin and the sickling of erythrocytes. Sickle cell anaemia (SCA) is the most common and clinically severe form of SCD. It is caused by homozygosity of the sickle mutation HbS. The mutation persists within populations as heterozygosity in individuals confers protection against malaria. Every year around 305,800 babies are born with SCD worldwide, with nearly 75% of these births occurring in sub-Saharan Africa.
The clinical expression of SCD is extremely heterogeneous. Features that vary include severity of anaemia, the frequency of painful vaso-occlusive crises, stroke, and mortality. Evidence has shown that genetic and non-genetic factors impact the severity of SCD. For example, high levels of fetal haemoglobin (HbF) associate with less severe SCD. In addition, co-inheritance of α-thalassemia is protective against some SCD-related complications, such as haemolysis, stroke and kidney disease
The availability of comprehensive medical treatment for SCD in high income countries, usually lessens morbidity and enables longer survival of SCD patients. However, due to inappropriate care and other compounding factors such as malaria, malnutrition and poverty, most cases of SCD do not fare as well.
Researchers have previously found that different HBB haplotypes associate with variable clinical expression of SCD. In this study, researchers used whole-exome sequencing data to explore whether rare gene-associated and function-altering variants associated with SCA clinical sub-phenotypes. They also wanted to determine whether these could lead to potential modifiable pathophysiological pathways. To do this, they studied two distinct clinical SCA groups. This included a ‘long survivor’ group (over 40 years) and a ‘stroke’ group (at least one episode of overt stroke). These groups were compared with a ‘random’ group (patients younger than 40 years without overt cerebrovascular disease). Researchers used this group to infer key genes and pathways. These 105 SCA patients were also compared with 58 ethnically matched homozygous haemoglobin A controls.
Their main finding was the significant differences observed in gene sets that were enriched for deleterious and loss-of-function mutations in phenotypically defined groups of patients. For example, in the ‘stroke’ group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation. This included the SERPINC1 gene, which encodes antithrombin, implicating loss of this gene activity with increased blood coagulation. Significantly, in the ‘long survivor’ group, genes such as CLCN6 and OGHDL, were enriched for deleterious/loss-of-function variants. The CLCN6 gene is associated with lower blood pressure which the team suggest is the reason these patients live longer. In addition, O6HDL is important for the metabolism of amino acid arginine, which is a key factor in the haemolysis-endothelial dysfunction observed in SCD. As a result, it has become a key target for therapeutic interventions.
This study provides support for the complexity of the genetic architecture of SCD phenotypic variability. It suggests that long survival is characterised by mutations that confer protection for adverse phenotypes e.g. stroke. It also highlights that the overt stroke phenotype in SCA is linked with mutations in genes involved in the complement and coagulation cascade. The team believes that this study significantly contributes to understanding the clinical heterogeneity of SCA which in turn will help with the design of new therapeutics.
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