We all learned in medical school that hemoglobinopathies are prevalent, at least in part, because carriers benefit from protection against malaria. It is well established that both sickle cell trait and α+-thalassemia alter red cell physiology to put the parasite at a disadvantage. Sickle cell trait may attenuate malarial infection by reducing intracellular oxygen tension or by targeting parasite-infected cells for splenic clearance. The protective mechanism of α+-thalassemia is even less certain, but the phenomenology is undisputed. In this article, the authors asked whether the combination of sickle cell trait and α+-thalassemia (HbAS, -α/-α) would be more protective than either trait alone. Their surprising finding was that patients carrying both hemoglobinopathy traits had little more protection than individuals who had neither.
This is an elegant example of negative epistasis. Epistasis is a genetic term that describes a situation in which the effect of a change in one gene depends on what is happening in a second, unrelated gene. The Bombay blood group phenotype is a familiar example of this effect. Individuals homozygous for the Bombay phenotype lack the ability to make a precursor molecule that is needed for attachment of both A and B antigens. As a result, their genes may dictate that they should have an A or B phenotype, but the Bombay gene overrules and the blood types as O. In the situation described in this article, the α+-thalassemia genotype abrogates the strong protective effect of HbAS. The mechanism for this negative epistasis is uncertain, but the authors hypothesize that it may result from greater affinity of the α globin polypeptide for the normal β globin polypeptide. Decreased α globin in the cell might thus change the relative amounts of HbA and HbS, effectively decreasing the intracellular concentration of HbS. While this compromises protection against malaria, the co-existence of α+-thalassemia and sickle cell genes in the same gene pool may have a beneficial effect in ameliorating the anemia of sickle cell disease.
