Functional Annotation of Genetic Loci Associated With Sepsis Prioritizes Immune and Endothelial Cell Pathways.

Kieu T T Le,Vasiliki Matzaraki,Cisca Wijmenga,Vinod Kumar,Jill Moser,Mihai G Netea

doi:10.3389/fimmu.2019.01949

Abstract

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 FER and MAN2A1 affect endothelial response to stimulation, indicating that both FER and MAN2A1 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.

Highlights

Sepsis is a major global health problem primarily caused by bacterial and fungal infections
We took advantage of existing molecular data and integrative functional genomics approach to reveal potential causal genes and pathways associated with sepsis heterogeneity
We show that

Summary

Introduction

Sepsis is a major global health problem primarily caused by bacterial and fungal infections. It is a life-threatening organ dysfunction characterized by a dysregulated host immune response [1]. Current strategies using a “one-size-fits-all” treatment approach for sepsis have failed because of the extreme heterogeneity in disease outcome [3]. It is becoming increasingly clear that the heterogeneity is determined. Sepsis Genetics Prioritizes Endothelial Pathways by impact of multiple risk factors including host genetic variation and pathogens [2]. Identifying the critical genetic factors that affect sepsis patient outcome will help us to unravel genetic mechanisms that determine sepsis heterogeneity

Methods

Results

Conclusion