title: Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait.
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.
authors.affiliation: 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
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Tabitha W
authors.initials: TW
authors.lastname: Mwangi
authors.forename: Sammy
authors.initials: S
authors.lastname: Wambua
authors.forename: Timothy E A
authors.initials: TE
authors.lastname: Peto
authors.forename: David J
authors.initials: DJ
authors.lastname: Weatherall
authors.forename: Sunetra
authors.initials: S
authors.lastname: Gupta
authors.forename: Mario
authors.initials: M
authors.lastname: Recker
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Penman
authors.forename: Sophie
authors.initials: S
authors.lastname: Uyoga
authors.forename: Alex
authors.initials: A
authors.lastname: Macharia
authors.forename: Jedidah K
authors.initials: JK
authors.lastname: Mwacharo
authors.forename: Robert W
authors.initials: RW
authors.lastname: Snow
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
mesh_terms: D017954:Africa South of the Sahara / Q000453:epidemiology; D000818:Animals; D002648:Child; D015331:Cohort Studies; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000254:growth & development*; D012805:Sickle Cell Trait / Q000453:epidemiology / Q000235:genetics*; D017085:alpha-Thalassemia / Q000453:epidemiology / Q000235:genetics*
chemical_list: D006451:Hemoglobin, Sickle