Sickle Cell Disease as a Multifactorial Condition

Abstract 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. α‐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 α‐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.