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

William K. Scott, Felix Mba Medie, Felicia Ruffin, Batu K. Sharma-Kuinkel, Derek D. Cyr, Shengru Guo, Derek M. Dykxhoorn, Robert L. Skov, Niels E. Bruun, Anders Dahl, Christian J. Lerche, Andreas Petersen, Anders Rhod Larsen, Trine Kiilerich Lauridsen, Helle Krogh Johansen, Henrik Ullum, Erik Sørensen, Christian Hassager, Henning Bundgaard, Henrik C. SchønheyderChristian Torp-Pedersen, Louise Bruun Østergaard, Magnus Arpi, Flemming Rosenvinge, Lise T. Erikstrup, Mahtab Chehri, Peter Søgaard, Paal S. Andersen, Vance G. Fowler

Research output: Contribution to journalJournal articleResearchpeer-review

123 Downloads (Pure)

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.

Original languageEnglish
Article numbere1007667
JournalPLOS Genetics
Volume14
Issue number10
Number of pages22
ISSN1553-7390
DOIs
Publication statusPublished - 1. Oct 2018

Fingerprint

bacteremia
Medical Genetics
genetic variation
Staphylococcus aureus
gene
genes
Glutamine
sampling
glutamine
Clustered Regularly Interspaced Short Palindromic Repeats
Exome
nitric oxide
gender
gene expression
cells
logistics
regression analysis
allele
genome
metabolism

Keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Animals
  • Bacteremia
  • Female
  • Gene Frequency/genetics
  • Genetic Variation/genetics
  • Glutaminase/genetics
  • Humans
  • Male
  • Mice
  • Middle Aged
  • RAW 264.7 Cells
  • Risk Factors
  • Staphylococcal Infections/genetics
  • Staphylococcus aureus/pathogenicity
  • Transcriptome/genetics
  • Whole Exome Sequencing/methods

Cite this

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 Genetics, 14(10), [e1007667]. https://doi.org/10.1371/journal.pgen.1007667
Scott, William K. ; Medie, Felix Mba ; Ruffin, Felicia ; Sharma-Kuinkel, Batu K. ; Cyr, Derek D. ; Guo, Shengru ; Dykxhoorn, Derek M. ; Skov, Robert L. ; Bruun, Niels E. ; Dahl, Anders ; Lerche, Christian J. ; Petersen, Andreas ; Larsen, Anders Rhod ; Lauridsen, Trine Kiilerich ; Johansen, Helle Krogh ; Ullum, Henrik ; Sørensen, Erik ; Hassager, Christian ; Bundgaard, Henning ; Schønheyder, Henrik C. ; Torp-Pedersen, Christian ; Østergaard, Louise Bruun ; Arpi, Magnus ; Rosenvinge, Flemming ; Erikstrup, Lise T. ; Chehri, Mahtab ; Søgaard, Peter ; Andersen, Paal S. ; Fowler, Vance G. / Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia. In: PLOS Genetics. 2018 ; Vol. 14, No. 10.
@article{482234e653fa48a2ae06b143e44c59ea,
title = "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.",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Animals, Bacteremia, Female, Gene Frequency/genetics, Genetic Variation/genetics, Glutaminase/genetics, Humans, Male, Mice, Middle Aged, RAW 264.7 Cells, Risk Factors, Staphylococcal Infections/genetics, Staphylococcus aureus/pathogenicity, Transcriptome/genetics, Whole Exome Sequencing/methods",
author = "Scott, {William K.} and Medie, {Felix Mba} and Felicia Ruffin and Sharma-Kuinkel, {Batu K.} and Cyr, {Derek D.} and Shengru Guo and Dykxhoorn, {Derek M.} and Skov, {Robert L.} and Bruun, {Niels E.} and Anders Dahl and Lerche, {Christian J.} and Andreas Petersen and Larsen, {Anders Rhod} and Lauridsen, {Trine Kiilerich} and Johansen, {Helle Krogh} and Henrik Ullum and Erik S{\o}rensen and Christian Hassager and Henning Bundgaard and Sch{\o}nheyder, {Henrik C.} and Christian Torp-Pedersen and {\O}stergaard, {Louise Bruun} and Magnus Arpi and Flemming Rosenvinge and Erikstrup, {Lise T.} and Mahtab Chehri and Peter S{\o}gaard and Andersen, {Paal S.} and Fowler, {Vance G.}",
year = "2018",
month = "10",
day = "1",
doi = "10.1371/journal.pgen.1007667",
language = "English",
volume = "14",
journal = "P L o S Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "10",

}

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 2018, 'Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia', PLOS Genetics, vol. 14, no. 10, e1007667. https://doi.org/10.1371/journal.pgen.1007667

Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia. / Scott, William K.; Medie, Felix Mba; Ruffin, Felicia; Sharma-Kuinkel, Batu K.; Cyr, Derek D.; Guo, Shengru; Dykxhoorn, Derek M.; Skov, Robert L.; Bruun, Niels E.; Dahl, Anders; Lerche, Christian J.; Petersen, Andreas; Larsen, Anders Rhod; Lauridsen, Trine Kiilerich; Johansen, Helle Krogh; Ullum, Henrik; Sørensen, Erik; Hassager, Christian; Bundgaard, Henning; Schønheyder, Henrik C.; Torp-Pedersen, Christian; Østergaard, Louise Bruun; Arpi, Magnus; Rosenvinge, Flemming; Erikstrup, Lise T.; Chehri, Mahtab; Søgaard, Peter; Andersen, Paal S.; Fowler, Vance G.

In: PLOS Genetics, Vol. 14, No. 10, e1007667, 01.10.2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia

AU - Scott, William K.

AU - Medie, Felix Mba

AU - Ruffin, Felicia

AU - Sharma-Kuinkel, Batu K.

AU - Cyr, Derek D.

AU - Guo, Shengru

AU - Dykxhoorn, Derek M.

AU - Skov, Robert L.

AU - Bruun, Niels E.

AU - Dahl, Anders

AU - Lerche, Christian J.

AU - Petersen, Andreas

AU - Larsen, Anders Rhod

AU - Lauridsen, Trine Kiilerich

AU - Johansen, Helle Krogh

AU - Ullum, Henrik

AU - Sørensen, Erik

AU - Hassager, Christian

AU - Bundgaard, Henning

AU - Schønheyder, Henrik C.

AU - Torp-Pedersen, Christian

AU - Østergaard, Louise Bruun

AU - Arpi, Magnus

AU - Rosenvinge, Flemming

AU - Erikstrup, Lise T.

AU - Chehri, Mahtab

AU - Søgaard, Peter

AU - Andersen, Paal S.

AU - Fowler, Vance G.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Animals

KW - Bacteremia

KW - Female

KW - Gene Frequency/genetics

KW - Genetic Variation/genetics

KW - Glutaminase/genetics

KW - Humans

KW - Male

KW - Mice

KW - Middle Aged

KW - RAW 264.7 Cells

KW - Risk Factors

KW - Staphylococcal Infections/genetics

KW - Staphylococcus aureus/pathogenicity

KW - Transcriptome/genetics

KW - Whole Exome Sequencing/methods

U2 - 10.1371/journal.pgen.1007667

DO - 10.1371/journal.pgen.1007667

M3 - Journal article

C2 - 30289878

AN - SCOPUS:85055078478

VL - 14

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 10

M1 - e1007667

ER -