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: Samuel B Anyona, Prakasha Kempaiah, Evans Raballah, Collins Ouma, Tom Were, Gregory C Davenport, Stephen N Konah, John M Vulule, James B Hittner, Charity W Gichuki, John M Ong'echa, Douglas J Perkins
• Journal: Infection and immunity (Infect Immun) Vol. 79 Issue 12 Pg. 4923-32 (Dec 2011) ISSN: 1098-5522 [Electronic] United States
• PMID: 21969001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-18

Topics

• Anemia (etiology)
• Female
• Gene Expression Regulation (physiology)
• Genetic Testing
• Genetic Variation
• Haplotypes (genetics)
• Humans
• Infant
• Infant Mortality
• Interleukin-18 (genetics)
• Kenya (epidemiology)
• Linkage Disequilibrium
• Malaria, Falciparum (complications, epidemiology, mortality)
• Male
• Odds Ratio
• Promoter Regions, Genetic (genetics)
• Risk Factors