| dc.description.abstract | Immune naïve children residing in endemic Plasmodium falciparum (P. falciparum) transmission regions experience repeated episodes of malaria infection that may lead to bone marrow suppression and subsequently severe malaria anemia that is responsible for the high morbidity and mortality in these regions. Genetic variation in cytokine genes play a key role in influencing malaria infection outcomes by altering production of immune inflammatory mediators. The current study determined the association of genetic variants in IL7 (72194T>C and -2440A>G) and CSF2 (-7032G>A, and 64544T>C) with P. falciparum malaria infection outcomes in children attending Siaya County Referral Hospital (SCRH). Specifically, the study assessed the associations of genetic variants in IL7 with susceptibility to inefficient erythropoiesis (IE) and SMA; the influence of genetic variants in CSF2 on the rate of malaria infections and SMA episodes; the relationship between genetic variants in CSF2 and the risk of malaria infections and SMA episodes; and genetic variants in CSF2 and the risk of all-cause mortality, in falciparum parasitemic children (aged <36 months). The study designs were cross-sectional case control to achieve objective 1 (n=883) and longitudinal case control to achieve objectives 2-4 (n=1654). The current study utilized the archived samples ((n=2537) obtained from children enrolled in 2009-2012 in a study that evaluated genetic basis of SMA in children attending SDH. Genomic deoxyribonucleic acid was extracted from buccal swabs using the Gentra System and genotyped using a TaqMan 5’ allelic discrimination Assay-By-Design method. Cross-sectional data was analyzed using SPSS (Version 24.0) while longitudinal data was analyzed using R (version 3.1.4). One-way analysis of variance and Student’s t-test were used to compare means. Mann-Whitney-U test was used for pairwise comparisons of median. Chi square and Fisher’s exact test were used to find differences in proportions of genetic variants. Binomial logistic regression was used to determine associations of genetic variants in IL7 with susceptibility to IE and SMA. Poisson regression was used to determine the influence of genetic variants in CSF2 on the rate of in malaria infections and SMA episodes. Cox proportional hazard model was used to determine the relationship between genetic variants in CSF2 and the risk of malaria infections, SMA episodes and all-cause mortality. P values ≤0.05 were considered significant. The results showed that carriage of IL77 2194 TC genotype was associated with enhanced susceptibility to IE (Odds ratio (OR) =1.90; 95% (confidence interval (CI) 1.09–3.30; P=0.02) as was homozygous CC genotype (OR 5.14; 95%CI=1.20–21.99; P=0.03). Individuals with the IL7 CA haplotype had an increased risk of IE (OR=1.90; 95%CI=1.10–3.30; P=0.02), whereas TA haplotype carriers were protected against IE (OR=0.24; 95%CI=0.06–1.21; P=0.05). Further, a decreased incidence rate ratio (IRR) for malaria was conferred by inheritance of the CSF264544 TC genotype (P=0.02) and CSF2 AC/GC diplotype (P<0.01). An increased IRR for malaria was observed in carriers of the CSF2 AT/GC diplotype (P=0.02), while the inheritance of the CSF2 AT haplotype increased the IRR for SMA (P=0.01). Decreased hazard rates (HR) for malaria were observed among CSF2 AC haplotype carriers (P<0.01) while inheritance of the CSF2-7032 GA genotype increased the HR for all-cause mortality (P=0.03). Cumulative results showed that variation in IL7 gene is associated with erythropoietic responses in children with falciparum malaria while variation in CSF2 gene influences susceptibility to malaria, SMA, and all-cause mortality, suggesting that genetic variations in IL7 and CSF2 are potential modulators and or predictors of malaria infection outcomes in young children residing in malaria endemic areas. The findings highlight novel immuno-genetic associations with malaria infection, IE, SMA and all-cause mortality that have potential to guide immunotherapy and vaccine design for severe malaria in young children. | en_US |
