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

Publication ,  Journal Article
Scott, WK; Medie, FM; Ruffin, F; Sharma-Kuinkel, BK; Cyr, DD; Guo, S; Dykxhoorn, DM; Skov, RL; Bruun, NE; Dahl, A; Lerche, CJ; Petersen, A ...
Published in: PLoS Genet
October 2018

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.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

October 2018

Volume

14

Issue

10

Start / End Page

e1007667

Location

United States

Related Subject Headings

  • Transcriptome
  • Staphylococcus aureus
  • Staphylococcal Infections
  • Risk Factors
  • RAW 264.7 Cells
  • Middle Aged
  • Mice
  • Male
  • Humans
  • Glutaminase
 

Citation

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Scott, W. K., Medie, F. M., Ruffin, F., Sharma-Kuinkel, B. K., Cyr, D. D., Guo, S., … Fowler, V. G. (2018). Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia. PLoS Genet, 14(10), e1007667. https://doi.org/10.1371/journal.pgen.1007667
Scott, William K., Felix Mba Medie, Felicia Ruffin, Batu K. Sharma-Kuinkel, Derek D. Cyr, Shengru Guo, Derek M. Dykxhoorn, et al. “Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia.PLoS Genet 14, no. 10 (October 2018): e1007667. https://doi.org/10.1371/journal.pgen.1007667.
Scott WK, Medie FM, Ruffin F, Sharma-Kuinkel BK, Cyr DD, Guo S, et al. Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia. PLoS Genet. 2018 Oct;14(10):e1007667.
Scott, William K., et al. “Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia.PLoS Genet, vol. 14, no. 10, Oct. 2018, p. e1007667. Pubmed, doi:10.1371/journal.pgen.1007667.
Scott WK, Medie FM, Ruffin F, Sharma-Kuinkel BK, Cyr DD, Guo S, Dykxhoorn DM, Skov RL, Bruun NE, Dahl A, Lerche CJ, Petersen A, Larsen AR, Lauridsen TK, Johansen HK, Ullum H, Sørensen E, Hassager C, Bundgaard H, Schønheyder HC, Torp-Pedersen C, Østergaard LB, Arpi M, Rosenvinge F, Erikstrup LT, Chehri M, Søgaard P, Andersen PS, Fowler VG. Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia. PLoS Genet. 2018 Oct;14(10):e1007667.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

October 2018

Volume

14

Issue

10

Start / End Page

e1007667

Location

United States

Related Subject Headings

  • Transcriptome
  • Staphylococcus aureus
  • Staphylococcal Infections
  • Risk Factors
  • RAW 264.7 Cells
  • Middle Aged
  • Mice
  • Male
  • Humans
  • Glutaminase