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A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans.

Publication ,  Journal Article
Jaeger, M; Matzaraki, V; Aguirre-Gamboa, R; Gresnigt, MS; Chu, X; Johnson, MD; Oosting, M; Smeekens, SP; Withoff, S; Jonkers, I; Perfect, JR ...
Published in: J Infect Dis
July 31, 2019

BACKGROUND: Candidemia, one of the most common causes of fungal bloodstream infection, leads to mortality rates up to 40% in affected patients. Understanding genetic mechanisms for differential susceptibility to candidemia may aid in designing host-directed therapies. METHODS: We performed the first genome-wide association study on candidemia, and we integrated these data with variants that affect cytokines in different cellular systems stimulated with Candida albicans. RESULTS: We observed strong association between candidemia and a variant, rs8028958, that significantly affects the expression levels of PLA2G4B in blood. We found that up to 35% of the susceptibility loci affect in vitro cytokine production in response to Candida. Furthermore, potential causal genes located within these loci are enriched for lipid and arachidonic acid metabolism. Using an independent cohort, we also showed that the numbers of risk alleles at these loci are negatively correlated with reactive oxygen species and interleukin-6 levels in response to Candida. Finally, there was a significant correlation between susceptibility and allelic scores based on 16 independent candidemia-associated single-nucleotide polymorphisms that affect monocyte-derived cytokines, but not with T cell-derived cytokines. CONCLUSIONS: Our results prioritize the disturbed lipid homeostasis and oxidative stress as potential mechanisms that affect monocyte-derived cytokines to influence susceptibility to candidemia.

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Published In

J Infect Dis

DOI

EISSN

1537-6613

Publication Date

July 31, 2019

Volume

220

Issue

5

Start / End Page

862 / 872

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Oxidative Stress
  • Microbiology
  • Interleukin-6
  • Humans
  • Host-Pathogen Interactions
  • Homeostasis
  • Group IV Phospholipases A2
  • Genomics
  • Genome-Wide Association Study
 

Citation

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Jaeger, M., Matzaraki, V., Aguirre-Gamboa, R., Gresnigt, M. S., Chu, X., Johnson, M. D., … Kumar, V. (2019). A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans. J Infect Dis, 220(5), 862–872. https://doi.org/10.1093/infdis/jiz206
Jaeger, Martin, Vasiliki Matzaraki, Raúl Aguirre-Gamboa, Mark S. Gresnigt, Xiaojing Chu, Melissa D. Johnson, Marije Oosting, et al. “A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans.J Infect Dis 220, no. 5 (July 31, 2019): 862–72. https://doi.org/10.1093/infdis/jiz206.
Jaeger M, Matzaraki V, Aguirre-Gamboa R, Gresnigt MS, Chu X, Johnson MD, et al. A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans. J Infect Dis. 2019 Jul 31;220(5):862–72.
Jaeger, Martin, et al. “A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans.J Infect Dis, vol. 220, no. 5, July 2019, pp. 862–72. Pubmed, doi:10.1093/infdis/jiz206.
Jaeger M, Matzaraki V, Aguirre-Gamboa R, Gresnigt MS, Chu X, Johnson MD, Oosting M, Smeekens SP, Withoff S, Jonkers I, Perfect JR, van de Veerdonk FL, Kullberg B-J, Joosten LAB, Li Y, Wijmenga C, Netea MG, Kumar V. A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans. J Infect Dis. 2019 Jul 31;220(5):862–872.
Journal cover image

Published In

J Infect Dis

DOI

EISSN

1537-6613

Publication Date

July 31, 2019

Volume

220

Issue

5

Start / End Page

862 / 872

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Oxidative Stress
  • Microbiology
  • Interleukin-6
  • Humans
  • Host-Pathogen Interactions
  • Homeostasis
  • Group IV Phospholipases A2
  • Genomics
  • Genome-Wide Association Study