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Nat Genet. 2005 Nov;37(11):1253-7. Epub 2005 Oct 16.

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

Author information

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

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.

PMID:
16227994
PMCID:
PMC3521056
DOI:
10.1038/ng1660
[Indexed for MEDLINE]
Free PMC Article

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