Negative epistasis between the malaria-protective effects of ⁺-thalassemia and the sickle cell trait

Thomas N Williams^1, 2, 3, Tabitha W Mwangi^1, 2, Sammy Wambua¹, Timothy E A Peto², David J Weatherall⁴, Sunetra Gupta⁵, Mario Recker⁵, Bridget S Penman⁵, Sophie Uyoga¹, Alex Macharia¹, Jedidah K Mwacharo¹, Robert W Snow^1, 2 & Kevin Marsh^1, 2

¹  Kenya Medical Research Institute/Wellcome Trust Programme, Centre for Geographic Medicine Research, Coast, PO Box 230, Kilifi District Hospital, Kilifi, Kenya.

²  Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.

³  Department of Paediatrics, John Radcliffe Hospital, Oxford OX3 9DS, UK.

⁴  Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.

⁵  Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria¹. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and ⁺-thalassemia, a condition characterized by reduced production of the normal -globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria^{2, 3, 4}, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying ⁺-thalassemia. Negative epistasis could explain the failure of ⁺-thalassemia to reach fixation in any population in sub-Saharan Africa.

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