Genetic variation in interleukin-7 is associated with a reduced erythropoietic response in Kenyan children infected with Plasmodium falciparum.

BACKGROUND: Severe malarial anemia (SMA) is a leading cause of malaria-related morbidity and mortality in children. The genetic factors that influence development of SMA and inefficient erythropoiesis, a central pathogenic feature of SMA, are only partially understood. METHODS: We performed a pilot Genome-wide Association Study (GWAS) on children with Plasmodium falciparum. The GWAS was performed using the Illumina® Infinium® HD Super Assay in conjunction with Illumina's® Human Omni2.5-8v1 BeadChip (with > 2.45 M markers). Data were analyzed using single SNP logistic regression analysis with an additive model of inheritance controlling for covariates. Results from our pilot global genomics study identified that variation in interleukin (IL)-7 was associated with enhanced risk of SMA. To validate this finding, we investigated the relationship between genotypes and/or haplotypes of two single nucleotide polymorphisms (SNPs) in IL7 [72194 T/C and - 2440 A/G] and susceptibility to both SMA and inefficient erythropoiesis [i.e., reticulocyte production index (RPI) < 2.0 in anemic children (Hb < 11.0 g/dL). Children presenting with P. falciparum malaria (< 3 years, n = 883) were stratified into two groups: Uncomplicated malaria (UM, n = 718) and SMA (n = 165). RESULTS: Regression modeling, controlling for anemia-related confounders, revealed that carriage of the TC genotype at position 72194 T/C was associated with enhanced susceptibility to inefficient erythropoiesis (OR = 1.90; 95% CI 1.09-3.30; P = 0.02) as was homozygous CC (OR 5.14; 95% CI = 1.20-21.99; P = 0.03). Consistent with this finding, individuals with the CA (72194C/-2440A) haplotype had an increased risk of inefficient erythropoiesis (OR = 1.90; 95% CI = 1.10-3.30; P = 0.02), whereas TA haplotype carriers had marginal protection against inefficient erythropoiesis (OR = 0.24; 95% CI = 0.06-1.21; P = 0.05). These observations were supported by Cochran-Armitage trend test for inefficient erythropoiesis (CA > TA > CG; P < 0.01). Although none of the genotype and/or haplotypic variants were significantly associated with SMA, the direction of the risk profiles were consistent with the erythropoiesis results. CONCLUSION: Taken together, variation in IL7 is associated with erythropoietic responses in children with falciparum malaria, a central physiological feature contributing to development of SMA.

Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya.

Plasmodium falciparum infections remain among the leading causes of morbidity and mortality in holoendemic transmission areas. Located within region 5q31.1, the colony-stimulating factor 2 gene (CSF2) encodes granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor that mediates host immune responses. Since the effect of CSF2 variation on malaria pathogenesis remains unreported, we investigated the impact of two genetic variants in the 5q31.1 gene region flanking CSF2:g-7032 G > A (rs168681:G > A) and CSF2:g.64544T > C (rs246835:T > C) on the rate and timing of malaria and severe malarial anemia (SMA, Hb < 5.0 g/dL) episodes over 36 months of follow-up. Children (n = 1654, aged 2-70 months) were recruited from a holoendemic P. falciparum transmission area of western Kenya. Decreased incidence rate ratio (IRR) for malaria was conferred by inheritance of the CSF2:g.64544 TC genotype (P = 0.0277) and CSF2 AC/GC diplotype (P = 0.0015). Increased IRR for malaria was observed in carriers of the CSF2 AT/GC diplotype (P = 0.0237), while the inheritance of the CSF2 AT haplotype increased the IRR for SMA (P = 0.0166). A model estimating the longitudinal risk of malaria showed decreased hazard rates among CSF2 AC haplotype carriers (P = 0.0045). Investigation of all-cause mortality revealed that inheritance of the GA genotype at CSF2:g-7032 increased the risk of mortality (P = 0.0315). Higher risk of SMA and all-cause mortality were observed in younger children (P < 0.0001 and P = 0.0015), HIV-1(+) individuals (P < 0.0001 and P < 0.0001), and carriers of HbSS (P = 0.0342 and P = 0.0019). Results from this holoendemic P. falciparum area show that variation in gene region 5q31.1 influences susceptibility to malaria, SMA, and mortality, as does age, HIV-1 status, and inheritance of HbSS.