Sickle Cell Disease as a Multi‐Factorial Condition

Abstract

The phenotype of sickle cell anaemia is heterogeneous. Although all patients have the identical sickle haemoglobin mutation, the type, severity and frequency of complications are variable. The products of epistatic modifying genes, along with environmental influences, interact to determine the disease phenotype. Haemoglobin F concentration and its distribution among erythrocytes are likely the most important genetic modulator of disease severity. Polymorphic variation in several genetic loci, including BCL11A in chromosome 2p, the HBS1L‐MYB locus in 6q23 and the C‐T polymorphism 5′ to HBG2 on chromosome 11p, are associated with differences in haemoglobin F gene expression. ZBTB7A in chromosome 19p, along with BCL11A, is a major suppressor of haemoglobin F expression. α‐Thalassaemia is the other major modulator of sickle cell disease. In addition to haemoglobin F and α‐thalassaemia, some evidence exists that genes influencing endothelial activation, inflammation, red blood cell hydration and haemostasis might contribute to phenotypic diversity.

Key Concepts

  • Sickle cell anaemia is a single‐gene disorder with heterogeneous clinical features.
  • The phenotype of sickle cell anaemia is affected by epistatic modifier genes.
  • Haemoglobin F is the best‐known genetic modifier of sickle cell anaemia.
  • Polymorphisms in three established quantitative trait loci modulate haemoglobin F.
  • High haemoglobin F levels are associated with reduced mortality and the rate of viscosity–vaso‐occlusive complications.
  • The locus of the haemoglobin F effect is the sickle erythrocyte.
  • The distribution of concentrations of haemoglobin F among sickle erythrocytes is likely to be the critical determinant of its clinical effects.
  • Co‐inheritance of α‐thalassaemia is associated with reduced rates of haemolysis and vasculopathic complications, but an increased incidence of viscosity–vaso‐occlusive manifestations.
  • Candidate gene and genome‐wide association studies have identified genes that potentially affect sickle cell disease phenotype by modifying disease pathogenesis.
  • It is likely that many genes, each playing a small role, contribute to the phenotypic heterogeneity of disease.

Keywords: sickle cell anaemia; epistasis; foetal haemoglobin; endothelium; erythrocyte; globin genes; SNPs; genetic association studies

Figure 1. Factors affecting the phenotype of sickle cell disease. The actions of different genes expressed in sickle erythrocytes (ISC, irreversibly sickled cells; RBC, sickle discocytes and R, stress reticulocytes), endothelial cells (EC), neutrophils (N) and genes that affect haemostasis may all influence the phenotype of sickle cell disease. Sickle vaso‐occlusion involves adhesion of sickle erythrocytes, neutrophils and sickle reticulocytes to each other and to the endothelium and sub‐endothelial tissue. Also involved are platelets, coagulation factors and sub‐endothelial elements that might be accessible due to endothelial damage and injury caused by migrating neutrophils. O2, oxygen‐free radicals; NOS, nitric oxide synthase; ICAMs, cell adhesion molecules; VCAMS, cell adhesion molecules; NO, nitric oxide; HbF, haemoglobin F and G6PD, glucose‐6‐phosphate dehydrogenase.
Figure 2. Effects of HbF concentration in F‐cells on the phenotype of sickle cell anaemia. F‐cells can be recognised if they contain about 6 pg. of HbF, but this amount of HbF does not fully protect the cell from HbS polymerisation under physiological conditions. Only when the sickle cell contains at least 10 pg. of HbF, it is fully protected. Even when the total HbF concentration in the blood is the same, the distribution of concentrations of HbF among F‐cell varies. This distribution and the number of protected cells determine the disease‐modulating potential of HbF. Reproduced with permission from Buchanan 2014 © American Society of Hematology.
Figure 3. Cis‐ and trans‐acting modulators of expression within the β‐globin gene cluster that play roles in globin gene switching. The Lbd (lim binding domain) 1 complex: (LDB1/LMO2/GATA1/Tal 1) occupies the LCR and gene promoters and facilitates looping to globin gene promoters. H3K9 methyltransferases cause methylation and repress gene transcription. Modified from Sankaran and Weiss 2015 © Nature Publishing Group.
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Steinberg, Martin H, and Verhovsek, Madeleine M(Sep 2017) Sickle Cell Disease as a Multi‐Factorial Condition. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006021.pub3]