Genome wide association study of Escherichia coli bloodstream infection isolates identifies genetic determinants for the portal of entry but not fatal outcome

Abstract

Escherichia coli is an important cause of bloodstream infections (BSI), which is of concern given its high mortality and increasing worldwide prevalence. Finding bacterial genetic variants that might contribute to patient death is of interest to better understand infection progression and implement diagnostic methods that specifically look for those factors. E. coli samples isolated from patients with BSI are an ideal dataset to systematically search for those variants, as long as the influence of host factors such as comorbidities are taken into account. Here we performed a genome-wide association study (GWAS) using data from 912 patients with E. coli BSI from hospitals in Paris, France. We looked for associations between bacterial genetic variants and three patient outcomes (death at 28 days, septic shock and admission to intensive care unit), as well as two portals of entry (urinary and digestive tract), using various clinical variables from each patient to account for host factors. We did not find any association between genetic variants and patient outcomes, potentially confirming the strong influence of host factors in influencing the course of BSI; we however found a strong association between the papGII operon and entrance of E. coli through the urinary tract, which demonstrates the power of bacterial GWAS when applied to actual clinical data. Despite the lack of associations between E. coli genetic variants and patient outcomes, we estimate that increasing the sample size by one order of magnitude could lead to the discovery of some putative causal variants. Given the wide adoption of bacterial genome sequencing of clinical isolates, such sample sizes may be soon available.

A statistical genomics framework to trace bacterial genomic predictors of clinical outcomes in Staphylococcus aureus bacteraemia

“…As expected, vancomycin MIC had a high heritability, while duration of bacteraemia and mortality had substantially lower values (Figure 2E and Table S1). These values are consistent bacterial GWAS of S. aureus infection vs. colonisation (Young, Wu et al 2021) and E. coli bacteraemia mortality (Denamur, Condamine et al 2022). We also sought to estimate the contribution of lineages to the phenotypic variance by extracting from the linear mixed model the variance attributed to the first 10 PC.…”

“…In a bacterial GWAS of a cohort of 912 patients with Escherichia coli bacteraemia, no bacterial genetic variant was associated with mortality, septic shock or intensive care unit admission. This correlated with very low heritability estimates for these outcomes (Denamur, Condamine et al 2022).…”

“…A deeper understanding of these outcome determinants would help design more effective treatments and inform precision medicine strategies. However, in contrast with progress in the immunogenetics of infections (Kwok, Mentzer et al 2021), it has been challenging to identify bacterial genetic factors influencing infection outcomes (Giulieri, Tong et al 2020, Denamur, Condamine et al 2022). This is due to the considerable genetic diversity of bacterial pathogens and the strong clonal structure of bacterial populations that complicate genome-wide association studies (GWAS) (Power, Parkhill et al 2017).…”

All Staphylococcus aureus bacteraemia strains have the potential to cause infective endocarditis: results of GWAS and experimental animal studies

“…Other studies using GWAS to explore the transition from nasal carriage of S. aureus to SAB have not identified genomic predictors of bacteraemia versus carriage, perhaps due to the possible polygenic nature of this transition (49,50). Denamur et al estimated that increasing sample size by an order of magnitude may provide enough power to detect subtle differences in a subset of strains (51). However, inclusion of such a number of patients will be challenging, and if genetic markers are identified, they are likely to be valid only for that one lineage (i.e., a specific ST or CC), and thus difficult to exploit in a diagnostic context.…”

“…Denamur et al . estimated that increasing sample size by an order of magnitude may provide enough power to detect subtle differences in a subset of strains (51). However, inclusion of such a number of patients will be challenging, and if genetic markers are identified, they are likely to be valid only for that one lineage (i.e., a specific ST or CC), and thus difficult to exploit in a diagnostic context.…”