Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait.
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| Abstract |
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.
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| Authors | Thomas N Williams, Tabitha W Mwangi, Sammy Wambua, Timothy E A Peto, David J Weatherall, Sunetra Gupta, Mario Recker, Bridget S Penman, Sophie Uyoga, Alex Macharia, Jedidah K Mwacharo, Robert W Snow, Kevin Marsh |
| Journal | Nature genetics (Nat Genet) Vol. 37 Issue 11 Pg. 1253-7 (Nov 2005) ISSN: 1061-4036 [Print] United States |
| PMID | 16227994 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't) |
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