Frequency distribution of cytokine and associated transcription factor single nucleotide polymorphisms in Zimbabweans: Impact on schistosome infection and cytokine levels

Abstract

Cytokines mediate T-helper (TH) responses that are crucial for determining the course of infection and disease. The expression of cytokines is regulated by transcription factors (TFs). Here we present the frequencies of single nucleotide polymorphisms (SNPs) in cytokine and TF genes in a Zimbabwean population, and further relate SNPs to susceptibility to schistosomiasis and cytokine levels. Individuals (N = 850) were genotyped for SNPs across the cytokines IL4, IL10, IL13, IL33, and IFNG, and their TFs STAT4, STAT5A/B, STAT6, GATA3, FOXP3, and TBX21 to determine allele frequencies. Circulatory levels of systemic and parasite-specific IL-4, IL-5, IL-10, IL-13, and IFNγ were quantified via enzyme-linked immunosorbent assay. Schistosoma haematobium infection was determined by enumerating parasite eggs excreted in urine by microscopy. SNP allele frequencies were related to infection status by case-control analysis and logistic regression, and egg burdens and systemic and parasite-specific cytokine levels by analysis of variance and linear regression. Novel findings were i) IL4 rs2070874*T’s association with protection from schistosomiasis, as carriage of ≥1 allele gave an odds ratio of infection of 0.597 (95% CIs, 0.421–0.848, p = 0.0021) and IFNG rs2069727*G’s association with susceptibility to schistosomiasis as carriage of ≥1 allele gave an odds ratio of infection of 1.692 (1.229–2.33, p = 0.0013). Neither IL4 rs2070874*T nor IFNG rs2069727*G were significantly associated with cytokine levels. This study found TH2-upregulating SNPs were more frequent among the Zimbabwean sample compared to African and European populations, highlighting the value of immunogenetic studies of African populations in the context of infectious diseases and other conditions, including allergic and atopic disease. In addition, the identification of novel infection-associated alleles in both TH1- and TH2-associated genes highlights the role of both in regulating and controlling responses to Schistosoma. Author summary Cytokines are known to modulate the course of infections and immune pathologies, the production of which is partly under genetic control. Genetic variation, such as single nucleotide polymorphisms (SNPs), are therefore known to influence phenotypes in infectious diseases. This study sought to understand how SNPs in genes encoding cytokines and associated transcription factors influence susceptibility and immune responses to schistosomiasis. Here, we report a range of SNPs upregulating immune responses being highly frequent among our Zimbabwean sample, and in addition identify two novel infection-associated loci. Firstly, the IL4 SNP rs2070874 T allele was identified as protective, while the IFNG SNP rs2069727 G allele was identified as a risk allele. Given the paucity of genetic studies focussing on African populations and neglected tropical diseases, our study provides a valuable contribution to our knowledge of the genetic control of schistosomiasis susceptibility with these findings. In addition, we highlight the role of genetics in modulating balance in immune responses and emphasise that further research focussing on African populations is required on this subject in order to improve our understanding of genetics, immune responses, and neglected diseases.