Sickle Cell Disease as a Multifactorial Condition

Madeleine M Verhovsek, McMaster University, Ontario, Canada
Martin H Steinberg, Boston University School of Medicine, Boston, Massachusetts, USA

Published online: September 2010

DOI: 10.1002/9780470015902.a0006021.pub2

The phenotype of sickle cell anaemia is heterogeneous. Although all patients have the identical sickle cell mutation, the type, severity and frequency of complications is variable. The products of epistatic modifying genes and the sickle haemoglobin gene, along with environmental influences, interact to determine the disease phenotype. Haemoglobin F concentration and distribution among erythrocytes is likely the most important genetic modulator of sickle cell disease severity. Several genetic loci are associated with haemoglobin F expression, including BCL11A in chromosome 2p, the HBS1L-MYB locus on 6q23, the C-T polymorphism 5¢ to HBG2 on chromosome 11p, and the olfactory receptor genes, OR51B6 and OR51B5, also on 11p. -Thalassaemia is another modulator of sickle cell disease. There is evidence that genes associated with endothelial activation, inflammation, red blood cell hydration and hemostasis might all play a role in 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.
  • Co-inheritance of -thalassaemia is associated with reduced rates of haemolysis and vasculopathic complications, but 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.

Keywords: sickle cell anaemia; epistasis; fetal 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 hemostasis 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 subendothelial tissue. Also involved are platelets, coagulation factors and subendothelial 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.
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Translation and Protein synthesis | Protein Folding, Evolution and Degradation | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Biomolecular Interactions | Proteins: Structure, Function, Metabolism
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Article Title: Sickle Cell Disease as a Multifactorial Condition
 
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Verhovsek, Madeleine M, and Steinberg, Martin H(Sep 2010) Sickle Cell Disease as a Multifactorial Condition. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006021.pub2]