Original Investigation

Human Genetics

, Volume 124, Issue 5, pp 515-524

First online:

Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production

  • Collins OumaAffiliated withCentre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases
  • , Gregory C. DavenportAffiliated withDepartment of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh
  • , Tom WereAffiliated withCentre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral DiseasesDepartment of Pathology, Kenyatta University
  • , Michael F. OtienoAffiliated withDepartment of Pre-Clinical Sciences, Kenyatta University
  • , James B. HittnerAffiliated withDepartment of Psychology, College of Charleston
  • , John M. VululeAffiliated withCentre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases
  • , Jeremy MartinsonAffiliated withDepartment of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh
  • , John M. Ong’echaAffiliated withCentre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral DiseasesDivision of Infectious Diseases, University of New Mexico School of Medicine
  • , Robert E. FerrellAffiliated withDepartment of Human Genetics, Graduate School of Public Health, University of Pittsburgh
    • , Douglas J. PerkinsAffiliated withCentre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral DiseasesDivision of Infectious Diseases, University of New Mexico School of Medicine Email author 

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Abstract

Plasmodium falciparum malaria is one of the leading global causes of morbidity and mortality with African children bearing the highest disease burden. Among the various severe disease sequelae common to falciparum malaria, severe malarial anemia (SMA) in pediatric populations accounts for the greatest degree of mortality. Although the patho-physiological basis of SMA remains unclear, dysregulation in inflammatory mediators, such as interleukin (IL)-10, appear to play an important role in determining disease outcomes. Since polymorphic variability in innate immune response genes conditions susceptibility to malaria, the relationship between common IL-10 promoter variants (−1,082A/G, −819T/C, and −592A/C), SMA (Hb < 6.0 g/dL), and circulating inflammatory mediator levels (i.e., IL-10, TNF-α, IL-6 and IL-12) were investigated in parasitemic Kenyan children (n = 375) in a holoendemic P. falciparum transmission area. Multivariate logistic regression analyses demonstrated that the −1,082G/−819C/−592C (GCC) haplotype was associated with protection against SMA (OR; 0.68, 95% CI, 0.43–1.05; = 0.044) and increased IL-10 production (= 0.029). Although none of the other haplotypes were significantly associated with susceptibility to SMA, individuals with the −1,082A/−819T/−592A (ATA) haplotype had an increased risk of SMA and reduced circulating IL-10 levels (= 0.042). Additional results revealed that the IL-10:TNF-α ratio was higher in the GCC group (= 0.024) and lower in individuals with the ATA haplotype (= 0.034), while the IL-10:IL-12 ratio was higher in ATA haplotype (= 0.006). Results presented here demonstrate that common IL-10 promoter haplotypes condition susceptibility to SMA and functional changes in circulating IL-10, TNF-α, and IL-12 levels in children with falciparum malaria.