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Reduced interferon (IFN)-α conditioned by IFNA2 (-173) and IFNA8 (-884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality

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dc.contributor.author Kempaiah, P
dc.contributor.author Anyona, SB
dc.contributor.author Raballah, E
dc.contributor.author Davenport, GC
dc.contributor.author Were, T
dc.contributor.author Hittner, JB
dc.contributor.author Ong'echa JM, JM
dc.contributor.author Perkins, DJ
dc.date.accessioned 2018-01-17T08:57:19Z
dc.date.available 2018-01-17T08:57:19Z
dc.date.issued 2012-08
dc.identifier.citation Kempaiah, P., Anyona, S. B., Raballah, E., Davenport, G. C., Were, T., Hittner, J. B., … Perkins, D. J. (2012). Reduced interferon (IFN)-α conditioned by IFNA2 (−173) and IFNA8 (−884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality. Human Genetics, 131(8), 1375–1391. http://doi.org/10.1007/s00439-012-1175-1 en_US
dc.identifier.uri https://repository.maseno.ac.ke/handle/123456789/120
dc.description.abstract Severe 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 mos.) 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 mos. 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 mortality. en_US
dc.language.iso en en_US
dc.publisher Pub Med Central en_US
dc.subject Interferon en_US
dc.subject promoter polymorphism en_US
dc.subject SMA en_US
dc.subject inflammatory mediators en_US
dc.title Reduced interferon (IFN)-α conditioned by IFNA2 (-173) and IFNA8 (-884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality en_US
dc.type Article en_US


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