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

Journal article

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, 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 alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.

Authors: Williams, T; Mwangi, T; Wambua, S; Peto, T; Weatherall, D

• Publication status: Published
• Journal: Nature genetics
• Volume: 37
• Issue: 11
• Pages: 1253-1257
• Publication date: 2005-11-01
• DOI: 10.1038/ng1660
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: alpha-Thalassemia; Humans; Incidence; Kenya; Animals; Heterozygote; Sickle Cell Trait; Malaria, Falciparum; Plasmodium falciparum; Cohort Studies; Africa South of the Sahara; Hemoglobin, Sickle; Child