Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality
In: Infection and Immunity, Jg. 79 (2011), Heft 12, S. 4923-4932
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Zugriff:
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 ...
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Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality
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Autor/in / Beteiligte Person: | Anyona, Samuel B. ; Kempaiah, Prakasha ; Raballah, Evans ; Ouma, Collins ; Were, Tom ; Davenport, Gregory C. ; Konah, Stephen N. ; Vulule, John M. ; Hittner, James B. ; Gichuki, Charity W. ; Ong'echa, John M. ; Perkins, Douglas J. ; Adams, J. H. |
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Zeitschrift: | Infection and Immunity, Jg. 79 (2011), Heft 12, S. 4923-4932 |
Veröffentlichung: | American Society for Microbiology, 2011 |
Medientyp: | academicJournal |
ISSN: | 0019-9567 |
DOI: | 10.1128/iai.05601-11 |
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