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dc.contributor.authorWere, T.
dc.contributor.authorKempaiah, P.
dc.contributor.authorAnyona, S. B.
dc.contributor.authorRaballah, E.
dc.contributor.authorDavenport, G. C.
dc.contributor.authorHittner, James B.
dc.contributor.authorOng'echa, J. M.
dc.contributor.authorPerkins, D. J.
dc.date.accessioned2013-12-17T12:40:17Z
dc.date.available2013-12-17T12:40:17Z
dc.date.issued2012-08
dc.identifier.citationPubMed, 131(8):1375-91, August 2012en_US
dc.identifier.urihttp://ir-library.ku.ac.ke/handle/123456789/8091
dc.descriptiondoi: 10.1007/s00439-012-1175-1en_US
dc.description.abstractSevere malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality in holoendemic Plasmodium falciparum transmission areas. Although dysregulation in cytokine production is an important etiology of SMA, the role of IFN-α in SMA has not been reported. As such, we investigated the relationship between IFN-α promoter polymorphisms [i.e., IFNA2 (A-173T) and IFNA8 (T-884A)], SMA, and functional changes in IFN-α production in children (n = 663; <36 months) residing in a holoendemic P. falciparum transmission region of Kenya. Children with SMA had lower circulating IFN-α than malaria-infected children without severe anemia (P = 0.025). Multivariate logistic regression analyses revealed that heterozygosity at -884 (TA) was associated with an increased risk of SMA [OR 2.80 (95 % CI 1.22-6.43); P = 0.015] and reduced IFN-α relative to wild type (TT; P = 0.038). Additional analyses demonstrated that carriage of the -173T/-884A (TA) haplotype was associated with increased susceptibility to SMA [OR 3.98 (95 % CI 1.17-13.52); P = 0.026] and lower IFN-α (P = 0.031). Follow-up of these children for 36 months revealed that carriers of TA haplotype had greater all-cause mortality than non-carriers (P < 0.001). Generation of reporter constructs showed that the IFNA8 wild-type -884TT exhibited higher levels of luciferase expression than the variant alleles (P < 0.001). Analyses of malaria-associated inflammatory mediators demonstrated that carriers of TA haplotype had altered production of IL-1β, MIG, and IL-13 compared to non-carriers (P < 0.050). Thus, variation at IFNA2 -173 and IFNA8 -884 conditions reduced IFN-α production, and increased susceptibility to SMA and mortalityen_US
dc.language.isoenen_US
dc.publisherPubMeden_US
dc.titleReduced interferon (IFN) –α conditioned by IFNA2 (-173) and IFNA8 (-884) haplotypes is associated with enhanced susceptibility to severe malarial anaemia and longitudinal all-cause mortalityen_US
dc.typeArticleen_US


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