Institute of Immunology & Infection Research, University of Edinburgh, Ashworth Laboratories, Edinburgh, United Kingdom.
NIHR Global Health Research Unit Tackling Infections to Benefit Africa (TIBA), University of Edinburgh, Ashworth Laboratories, Edinburgh, United Kingdom.
PLoS Negl Trop Dis. 2022 Jun 27;16(6):e0010536. doi: 10.1371/journal.pntd.0010536. eCollection 2022 Jun.
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 rs2070874T'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 rs2069727G'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 rs2070874T nor IFNG rs2069727G 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.
细胞因子介导辅助性 T 细胞（TH）反应，对于确定感染和疾病的进程至关重要。细胞因子的表达受转录因子（TFs）调控。本研究在津巴布韦人群中检测细胞因子和 TF 基因的单核苷酸多态性（SNPs）频率，并进一步将 SNPs 与血吸虫病易感性和细胞因子水平相关联。对 850 名个体进行了细胞因子 IL4、IL10、IL13、IL33 和 IFNG 及其 TFs STAT4、STAT5A/B、STAT6、GATA3、FOXP3 和 TBX21 的 SNPs 基因分型，以确定等位基因频率。通过酶联免疫吸附试验定量检测系统性和寄生虫特异性的 IL-4、IL-5、IL-10、IL-13 和 IFNγ 水平。通过显微镜检查尿液中寄生虫卵的数量来确定血吸虫感染情况。通过病例对照分析和逻辑回归分析 SNP 等位基因频率与感染状态的关系，通过方差分析和线性回归分析卵负荷和系统性及寄生虫特异性细胞因子水平。本研究的新发现包括：i）IL4 rs2070874T 与血吸虫病的保护相关，携带≥1 个等位基因的感染比值比为 0.597（95%置信区间，0.421-0.848，p=0.0021），IFNG rs2069727G 与血吸虫病的易感性相关，携带≥1 个等位基因的感染比值比为 1.692（1.229-2.33，p=0.0013）。IL4 rs2070874T 和 IFNG rs2069727G 均与细胞因子水平无显著相关性。本研究发现，与非洲和欧洲人群相比，津巴布韦人群中 TH2 上调 SNP 更为常见，这突显了在传染病和其他疾病（包括过敏和特应性疾病）背景下对非洲人群进行免疫遗传学研究的重要性。此外，在 TH1 和 TH2 相关基因中发现新的感染相关等位基因，突出了两者在调节和控制对血吸虫的反应中的作用。
