title: Functional promoter haplotypes of interleukin-18 condition susceptibility to severe malarial anemia and childhood mortality.
abstract: Severe malarial anemia (SMA) is a leading cause of morbidity and mortality in children residing in regions where Plasmodium falciparum transmission is holoendemic. Although largely unexplored in children with SMA, interleukin-18 (IL-18) is important for regulating innate and acquired immunity in inflammatory and infectious diseases. As such, we selected two functional single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (-137G→C [rs187238] and -607C→A [rs1946518]) whose haplotypes encompass significant genetic variation due to the presence of strong linkage disequilibrium among these variants. The relationship between the genotypes/haplotypes, SMA (hemoglobin [Hb], <5.0 g/dl], and longitudinal clinical outcomes were then investigated in Kenyan children (n = 719). Multivariate logistic regression analyses controlling for age, gender, sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, HIV-1, and bacteremia revealed that carriage of the -607AA genotype was associated with protection against SMA (odds ratio [OR] = 0.440 [95% confidence interval {CI} = 0.21 to 0.90], P = 0.031) in children with acute infection. In contrast, carriers of the -137G/-607C (GC) haplotype had increased susceptibility to SMA (OR = 2.050 [95% CI = 1.04 to 4.05], P = 0.039). Measurement of IL-18 gene expression in peripheral blood leukocytes demonstrated that elevated IL-18 transcripts were associated with reduced hemoglobin concentrations (ρ = -0.293, P = 0.010) and that carriers of the "susceptible" GC haplotype had elevated IL-18 transcripts (P = 0.026). Longitudinal investigation of clinical outcomes over a 3-year follow-up period revealed that carriers of the rare CC haplotype (∼1% frequency) had 5.76 times higher mortality than noncarriers (P = 0.001). Results presented here demonstrate that IL-18 promoter haplotypes that condition elevated IL-18 gene products during acute infection are associated with increased risk of SMA. Furthermore, carriage of the rare CC haplotype significantly increases the risk of childhood mortality.
authors.affiliation: University of New Mexico/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Anyona
authors.forename: Prakasha
authors.initials: P
authors.lastname: Kempaiah
authors.forename: Evans
authors.initials: E
authors.lastname: Raballah
authors.forename: Collins
authors.initials: C
authors.lastname: Ouma
authors.forename: Tom
authors.initials: T
authors.lastname: Were
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Davenport
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Konah
authors.forename: John M
authors.initials: JM
authors.lastname: Vulule
authors.forename: James B
authors.initials: JB
authors.lastname: Hittner
authors.forename: Charity W
authors.initials: CW
authors.lastname: Gichuki
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 / Q000209:etiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005820:Genetic Testing; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D020382:Interleukin-18 / Q000235:genetics*; D007630:Kenya / Q000453:epidemiology; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum / Q000150:complications* / Q000453:epidemiology / Q000401:mortality; D008297:Male; D016017:Odds Ratio; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D020382:Interleukin-18