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

摘要

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. Author summary Complications from bloodstream infection with Staphylococcus aureus (S . aureus) are important causes of hospitalization, significant illness, and death. The causes of these complications are not well understood, but likely involve genetic factors rendering people more susceptible to such infections, differences in the bacteria that cause the infection, and the interactions between them. We examined the parts of the human genome that code for proteins to find variations that were more common in people with complicated S . aureus bacteremia (SAB), and identified one gene, called GLS2 , in which variation is more common in complicated SAB cases than uncomplicated cases. Expression of GLS2 is lower in people with SAB than controls and in mouse white blood cells exposed to S . aureus . GLS2 encodes a protein that regulates the metabolism of glutamine, a regulatory process that activates white blood cells. These cells are very important in the immune response to S . aureus infection, and therefore genetic variants that might influence their growth are important potential genetic risk factors for complicated SAB.