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-1S) 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 [rs187238J and -607-CA [rs1946518J) 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 [HbJ, <5.0 g/dlJ, 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 [ORJ = 0.440 [95% confidence interval {CI} =0.21 to 0.90J, 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 4.05J, 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 (p = -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 mortallty.