Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia

Abstract

The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10−3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10−4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10−4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10−3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-β transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in leukocyte activation.

Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients

“…Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in patients despite appropriate antibiotic therapy is common, incompletely understood, and associated with poor clinical outcome (1–3). A growing body of evidence indicates that genetic variation may influence patient risk for S. aureus infection (4–7). In this investigation, we used a comprehensive approach to identify potential host genetic determinants of persistent methicillin-resistant S. aureus bacteremia (PB) and resolving methicillin-resistant S. aureus bacteremia (RB) in a large cohort of patients with S. aureus bacteremia (SAB).…”

Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease

“…Though sensitivity analyses indicated that glutamine’s causal estimate was primarily driven by influential SNP rs2657879, post-hoc analyses added weight to initial conclusions, with single-SNP replication as well as relaxed IV inclusion (with rs2657879 excluded) corroborating primary findings. Glutamine also has particular biological relevance as it is critically implicated in neuronal transmission as part of the glutamine-glutamate cycle (42, 44) (Supplementary Figure. S3).…”

“…It is also located within the genomic region of glutaminase-2 (GLS2), a protein-encoding gene for the enzyme responsible for converting glutamine to glutamate as part of the glutamineglutamate cycle (Supplementary Fig. S2-S3) (42)(43)(44). Moreover, it was the only reported GSH for glutamine in an earlier GWAS (p=6*10 -18 ), whereby glutamine was quantified using liquid-chromatography mass spectrometry (LCMS) in a sample of N=7,825 (45).…”

Risk stratification biomarkers for Staphylococcus aureus bacteraemia

“…Mortality rates for patients with Staphylococcus aureus bacteraemia (SAB) largely remain unchanged despite significant advances in clinical management, with new antibiotic therapies and rapid diagnostics available in recent decades. Significant heterogeneity in the clinical course of patients with SAB despite appropriate antibiotic therapy suggests that differential host immune response may contribute to adverse patient outcomes . However, critical determinants of immune evasion in patients with SAB remain poorly understood and connections between the immune response and microbiological failure are lacking.…”

“…Significant heterogeneity in the clinical course of patients with SAB despite appropriate antibiotic therapy suggests that differential host immune response may contribute to adverse patient outcomes. [1][2][3] However, critical determinants of immune evasion in patients with SAB remain poorly understood and connections between the immune response and microbiological failure are lacking. Previous studies identified several candidate innate immunity biomarkers that were independently associated with mortality and prolonged SAB, supporting the utility of biomarkers to distinguish patients prone to developing severe disease.…”