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.
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 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 mortality.
authors.affiliation: Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, MSC10-5550, Albuquerque, NM 87131-0001, USA. PKempaiah@salud.unm.edu
authors.forename: Prakasha
authors.initials: P
authors.lastname: Kempaiah
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Anyona
authors.forename: Evans
authors.initials: E
authors.lastname: Raballah
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Davenport
authors.forename: Tom
authors.initials: T
authors.lastname: Were
authors.forename: James B
authors.initials: JB
authors.lastname: Hittner
authors.forename: John M
authors.initials: JM
authors.lastname: Ong'echa
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Perkins
mesh_terms: D000740:Anemia / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D002423:Cause of Death; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D008137:Longitudinal Studies; D008288:Malaria / Q000209:etiology*; D008297:Male; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C554158:IFNA2 protein, human; C554164:IFNA8 protein, human; D016898:Interferon-alpha