Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Elife. 2022 Jul 22;11:e77461. doi: 10.7554/eLife.77461.
Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with parasitaemia. We construct a joint dataset including 1445 bacteraemia cases and 1143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data, we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so, we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.
侵袭性细菌病是非洲儿童发病率和死亡率的主要原因。尽管由多种病原体引起，但患有败血症的儿童在临床上彼此之间无法区分。尽管如此，迄今为止发现的大多数侵袭性感染的遗传易感性位点都是针对特定病原体的，因此不能提示细菌败血症具有共同的遗传结构。在这里，我们利用概率诊断模型来识别患有寄生虫血症的重症肯尼亚儿童中患有侵袭性细菌病的高概率儿童。我们构建了一个联合数据集，其中包括 1445 例菌血症病例和 1143 例严重疟疾病例，以及以前对人类遗传变异进行过基因分型的重症肯尼亚儿童的人群对照。使用这些数据，我们对侵袭性细菌感染进行了跨特征全基因组关联研究，根据细菌疾病的概率对病例进行加权。这样，我们确定并验证了一个与多种细菌病原体引起的侵袭性感染相关的新风险位点，该位点对疟疾风险没有明显影响。鉴定出的位点改变了刺激单核细胞中 的剪接，提示凋亡和自噬调节在肯尼亚儿童败血症发病机制中的作用。
