University of Groningen, University Medical Center Groningen, Genetics Department, Groningen, Netherlands.
Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
Front Immunol. 2019 Aug 14;10:1949. doi: 10.3389/fimmu.2019.01949. eCollection 2019.
Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated by three genome-wide association studies. However, genes from such suggestive loci may also provide crucial information to unravel genetic mechanisms that determine sepsis heterogeneity. Therefore, in this study, we made use of integrative approaches to prioritize genes and pathways affected by sepsis associated genetic variants. By integrating expression quantitative trait loci (eQTL) results from the largest whole-blood eQTL database, cytokine QTLs from pathogen-stimulated peripheral blood mononuclear cells (PBMCs), publicly available blood transcriptome data from pneumoniae-derived sepsis patients, and transcriptome data from pathogen-stimulated PBMCs, we identified 55 potential genes affected by 39 independent loci. By performing pathway enrichment analysis at these loci we found enrichment of genes for adherences-junction pathway. Finally, we investigated the functional role of the only one GWAS significant SNP rs4957796 on sepsis survival in altering transcription factor binding affinity in monocytes and endothelial cells. We also found that transient deficiency of and affect endothelial response to stimulation, indicating that both and could be the causal genes at this locus. Taken together, our study suggests that in addition to immune pathways, genetic variants may also affect non-immune related pathways.
由于脓毒症患者队列规模有限且存在极端异质性，仅有三项全基因组关联研究发现了一个显著的基因座和几个独立基因座的提示性关联。然而，这些提示性基因座上的基因也可能为阐明决定脓毒症异质性的遗传机制提供重要信息。因此，在这项研究中，我们采用综合方法来确定与脓毒症相关遗传变异相关的受影响基因和途径。通过整合来自最大的全血 eQTL 数据库的表达数量性状基因座 (eQTL) 结果、病原体刺激外周血单核细胞 (PBMC) 的细胞因子 QTL、来自肺炎相关性脓毒症患者的公开可用血液转录组数据以及病原体刺激 PBMC 的转录组数据，我们确定了 55 个受 39 个独立基因座影响的潜在基因。通过对这些基因座进行途径富集分析，我们发现与黏附连接途径相关的基因富集。最后，我们研究了全基因组关联研究中唯一显著的 SNP rs4957796 对脓毒症生存的影响，即其在改变单核细胞和内皮细胞中转录因子结合亲和力方面的作用。我们还发现和的短暂缺失会影响内皮细胞对刺激的反应，这表明这两个基因都可能是该基因座的因果基因。总之，我们的研究表明，除了免疫途径之外，遗传变异也可能影响非免疫相关途径。
