Interleukin-4 and STAT6 promoter polymorphisms but not interleukin-10 or 13 are essential for schistosomiasis and associated disease burden among Nigerian children

Abstract

Schistosomiasis is endemic in many parts of rural Africa, with previous reports showing interleukin-13 polymorphisms as drivers of infectivity and disease severity in West Africa while IL-13/IL-4 polymorphisms contributes to patterns of reinfection in East Africa. We have shown that there is a genetic delineation in susceptibility to and severity of infectious diseases in Africa, in addition to sub-continental differences in disease pattern. Therefore, which immunoregulatory biomarkers are essential in driving S. haematobium infection or regulate disease burden among Nigerian school children? One hundred and thirty one age and sex-matched schistosome-infected children and 275 uninfected controls, of same ethnicity, recruited from southwestern Nigeria, were screened for variability of cytokine genes, IL-10 (rs1800872), IL-13 (rs7719175), IL-4 (rs2243250) and STAT6 (rs3024974), utilizing a polymerase chain reaction-restriction fragment length polymorphism assay. We found no difference in genotypic or allelic frequencies of IL-10 and IL-13 promoter polymorphisms alone or in association with disease. Contrariwise, we report significant differences in the frequencies of IL-4 and STAT6 variants between groups. For IL-4, the rs2243250 T/T variant was significantly different for genotypes (71.6% versus 51.2%; p < .0004) and alleles (82.6% versus 71.1%; p < .001) between disease and control groups respectively. For STAT6 (rs3024974), the frequencies of genotypes C/C and C/T are 75.4% and 24.6%, both showing an association with disease; none of the infected subjects had the T/T variant. Despite minor differences in disease covariates, we found no association between IL-4 and STAT6 variants with age, gender or anemia. However, mean egg count (indicative of disease burden), was regulated based on IL-4 variants, with highest burden in infected subjects with rs2243250 T/T variant (mean egg count: 207.5 eggs/10 ml of urine) versus rs2243250 C/T heterozygotes (mean egg count: 84.3 eggs/10 ml of urine) versus rs2243250 C/C (mean egg count: 127.9 eggs/10 ml of urine). Comparing rs2243250 C/T versus rs2243250 T/T (p < .008) or rs2243250 C/C + C/T versus rs2243250 T/T (p < .016) reveals an association with disease burden. We conclude that the IL-4 promoter gene is a susceptibility factor for schistosomiasis, and essential to regulate disease burden, with worse disease among carriers of the rs2243250 T/T variant. The absence of the STAT6, rs3024974T/T variant among infected subjects reveal the necessity of the STAT6 promoter gene in driving susceptibility to schistosomiasis in Nigeria.

Keywords: Africa; Egg burden; IL-10; IL-13; Interleukin-4; STAT6; Schistosomiasis.