BACKGROUND Individuals genetically susceptible to high schistosomiasis worm burden may contribute disproportionately to transmission and could be prioritized for control. Identifying genes involved may guide development of therapy. METHODOLOGY/PRINCIPAL FINDINGS A cohort of 606 children aged 10-15 years were recruited in the Albert Nile region of Uganda and assessed for Schistosoma mansoni worm burden using the Up-Converting Particle Lateral Flow (UCP-LF) test detecting circulating anodic antigen (CAA), point-of-care Circulating Cathodic Antigen (POC-CCA) and Kato-Katz tests. Whole genome genotyping was conducted on 326 children comprising the top and bottom 25% of worm burden. Linear models were fitted to identify variants associated with worm burden in preselected candidate genes. Expression quantitative trait locus (eQTL) analysis was conducted for candidate genes with UCP-LF worm burden included as a covariate. Single Nucleotide Polymorphism loci associated with UCP-LF CAA included IL6 rs2066992 (OR = 0.43, p = 0.0006) and rs7793163 (OR = 2.0, p = 0.0007); IL21 SNP kgp513476 (OR 1.79, p = 0.0025) and IL17B SNP kgp708159 (OR = 0.35, p = 0.0028). A haplotype in the IL10 locus was associated with lower worm burden (OR = 0.53, p = 0.015) and overlapped SNPs rs1800896, rs1800871 and rs1800872. Significant haplotypes (p<0.05, overlapping significant SNP) associated with worm burden were observed in IL6 and the Th17 pathway IL12B and IL17B genes. There were significant eQTL in the IL6, IL5, IL21, IL25 and IFNG regions. CONCLUSIONS Variants associated with S. mansoni worm burden were in IL6, FCN2, RNASE3, IL10, IL12B and IL17B gene loci. However only eQTL associations remained significant after Bonferroni correction. In summary, immune balance, pathogen recognition and Th17 pathways may play a role in modulating Schistosoma worm burden. Individuals carrying risk variants may be targeted first in allocation of control efforts to reduce the burden of schistosomiasis in the community.

中文翻译：

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IL6、IL10、FCN2、RNA酶3、IL12B和IL17B基因座的变异与乌干达阿尔伯特尼罗河地区的曼氏血吸虫负担有关。

背景技术对高血吸虫病负荷具有遗传易感性的个体可能对传播做出不成比例的贡献，并且可以优先进行控制。识别相关基因可能会指导治疗的开发。方法/主要发现 在乌干达阿尔伯特尼罗河地区招募了 606 名 10-15 岁儿童队列，并使用检测循环阳极抗原 (CAA) 的上转换粒子侧向流 (UCP-LF) 测试来评估曼氏血吸虫负荷。 ）、护理点循环阴极抗原 (POC-CCA) 和 Kato-Katz 测试。对 326 名儿童进行了全基因组基因分型，这些儿童占蠕虫负担的最高和最低 25%。拟合线性模型来识别与预选候选基因中蠕虫负荷相关的变异。对候选基因进行表达数量性状位点 (eQTL) 分析，并将 UCP-LF 蠕虫负荷作为协变量。与 UCP-LF CAA 相关的单核苷酸多态性位点包括 IL6 rs2066992（OR = 0.43，p = 0.0006）和 rs7793163（OR = 2.0，p = 0.0007）；IL21 SNP kgp513476（OR 1.79，p = 0.0025）和 IL17B SNP kgp708159（OR = 0.35，p = 0.0028）。IL10 基因座中的单倍型与较低的蠕虫负荷相关（OR = 0.53，p = 0.015）以及重叠的 SNP rs1800896、rs1800871 和 rs1800872。在 IL6 和 Th17 通路 IL12B 和 IL17B 基因中观察到与蠕虫负荷相关的显着单倍型（p<0.05，重叠显着 SNP）。IL6、IL5、IL21、IL25 和 IFNG 区域存在显着的 eQTL。结论 与曼氏链球菌负担相关的变异存在于 IL6、FCN2、RNASE3、IL10、IL12B 和 IL17B 基因位点。然而，经过 Bonferroni 校正后，只有 eQTL 关联仍然显着。总之，免疫平衡、病原体识别和 Th17 通路可能在调节血吸虫负担中发挥作用。在分配控制工作以减轻社区血吸虫病负担时，携带风险变异的个体可能是首先的目标。