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.