Genetic modifiers of the beta-haemoglobin disorders

Abstract

Beta-thalassaemia and sickle cell disease (SCD) are two of the best-characterised human monogenic disorders, both resulting from mutations affecting the beta-globin gene. The central mechanism underlying the pathophysiology of β-thalassaemia is ineffective erythropoiesis arising from the redundant alpha-globin chains caused by a quantitative reduction in β-globin synthesis. In contrast, SCD is caused by the presence of a haemoglobin variant, haemoglobin S (HbS, α₂β^S₂) which results from a single nucleotide mutation (G<b>T</b>G to G<b>A</b>G) affecting codon 6 of the β-globin chain of haemoglobin (HbS, β cod 6 Glu→Val). Almost 300 mutations are now known to downregulate β-globin gene expression, while the sickle cell syndrome can arise from a combination of genotypes involving the interaction of the β^s allele with other variants of the β-globin gene (including β-thalassaemia). The causative genotypes are key determinants of disease severity. However, within each genotypic group, despite identical mutations, the frequency and severity of complications still vary considerably. Extensive biochemical and pathophysiological studies over the last 50–60 years have identified two major modifiers— inherent ability to produce fetal haemoglobin and co-inheritance of α-thalassaemia—both of which have been validated by population and family genetic studies. Elucidation of these two genetic modifiers has not been too difficult as they have a major impact on the pathophysiology of both diseases at the primary level, and the variants are common, but they do not explain the complete complex genotype/phenotype correlation. In the last 20 years, scientific research has applied several genetic approaches to dissect some of the modifiers that modulate complications at the secondary level. Genetic studies have been successful in identifying modifiers if the loci have a strong effect and if the genetic variants are common, for example influence of the <i>UGT1A1</i> promoter variants on bilirubin levels and predisposition to gallstones in both SCD and β-thalassaemia. It is possible that additional genetic modifiers could be uncovered using genetic approaches but success will depend on large sets of well-characterised patients with well-defined phenotypes. The lecture will highlight recent genetic studies and the key genetic modifiers uncovered in both disorders.