A genome-wide association study of survival in patients with sepsis

Abstract

Background Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. Methods This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10−8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants. Findings We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37–6.78], p = 4.92 × 10−8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury. Interpretation We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.

eQTLs identify regulatory networks and drivers of variation in the individual response to sepsis

“…We queried the Open Target Genetics portal 33,34 to look up previously reported associations for immune/inflammatory diseases and blood cell traits for SNPs of interest. We also obtained a list of SNPs associated with mortality in sepsis from Le et al 2019 110 and Hernandez-Beeftink et al 2022 26 to compare to our SRS GWAS results.…”

“…Host genetic background is a plausible driver of variation in the response to infection 15–18 , and in this regard use of genome-wide association studies and rare variant analysis has proved highly informative in severe COVID-19 19–23 . While these approaches have also been applied in sepsis 16,17,24–26 , they have been less successful, again likely due to disease heterogeneity. We hypothesise that the host response to sepsis, as represented by the transcriptomic SRS subgroups, has a polygenic basis with additional environmental modulators, and that elucidation of these underlying regulatory networks will be key in understanding inter-individual variation in disease responses and identifying treatable traits 27 .…”

Surviving Sepsis Campaign Research Priorities 2023

“…While studies support a role for genetic (243)(244)(245)(246)(247)(248) and epigenetic (249)(250)(251)(252)(253)(254)(255) factors in sepsis, the topic remains relatively unexplored. Despite years of research in this domain, we do not yet fully understand the link between genetic factors and susceptibility, severity and evolution of sepsis.…”

Analysis of comprehensive biomolecules in critically ill patients via bioinformatics technologies

“…performed a GWAS meta‐analysis using whole blood from two sepsis groups and reported that the SAMD9 genetic single nucleotide polymorphism (rsID:rs34896991) was associated with survival. 20 Scicluna et al. performed an unsupervised clustering analysis based on whole blood comprehensive RNA gene expression from three sepsis groups to elucidate four subtypes (MARS1‐4 groups) with different prognoses.…”