Minireview: Genetic basis of heterogeneity and severity in sickle cell disease

Abstract

Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease complications. In this review, we focus on the genetic modifiers of disease heterogeneity. The phenotypic heterogeneity of disease is only partially explained by genetic variability of fetal hemoglobin gene expression and co-inheritance of α thalassemia. Given the complexity of pathophysiology, many different definitions of severity are possible complicating a full understanding of its genetic foundation. The pathophysiological complexity and the interlocking nature of the biological processes underpinning disease severity are becoming better understood. Nevertheless, useful genetic signatures of severity, regardless of how this is defined, are insufficiently developed to be used for treatment decisions and for counseling.

Keywords: Severity in sickle cell disease; genome-wide association study; genotype–phenotype correlation; hemolysis; single nucleotide polymorphisms; subphenotypes of sickle cell disease.

Figure 1

Mechanism of sickle vasoocclusion. Erythrocyte damage and deformation (sickling) occur as a result of polymerization of deoxyHbS and also high concentrations of unpolymerized oxidized HbS, modulated by cellular levels of HbF, erythrocyte cation and water content, pH, temperature, and mechanical stresses that result in membrane damage and eventual failure. Hemolytic anemia and vasoocclusion cause tissue hypoxia. When this occlusion resolved and perfusion is established in the hypoxic tissue, free radicals are produced. These free radicals cause damage to the endothelia making them sticky for RBCs and also for leucocytes. The vascular wall ultimately becomes more vulnerable to occlusion (A color version of this figure is available in the online journal)

Figure 2

Hemolysis-endothelial dysfunction. With intravascular hemolysis, erythrocytes release hemoglobin and arginase. Arginine is the precursor for NO production by the endothelium via NOS3. Arginase degrades L-arginine, the NOS3 substrate causing reduced NO production. Free plasma hemoglobin interacts with NO producing methemoglobin and nitrate depleting NO. These mechanisms occur during steady state and the amount of intravascular hemolysis varies among patients. An additional mechanism which occurs commonly during vasoocclusive episodes relates to free radicals production with the oxidation of NO. NO depletions will disturb the vasodilatorvasoconstrictor balance, ultimately leading to vasoconstriction of the blood vessels which will complicate the VOC further (A color version of this figure is available in the online journal)