Cytokine gene polymorphisms and the outcome of invasive candidiasis: A prospective cohort study

Melissa D. Johnson, Theo S. Plantinga, Esther Van De Vosse, Digna R. Velez Edwards, P. Brian Smith, Barbara D. Alexander, John C. Yang, Dennis Kremer, Gregory Laird, Marije Oosting, Leo A B Joosten, Jos W M Van Der Meer, Jaap T. Van Dissel, Thomas J. Walsh, John R. Perfect, Bart Jan Kullberg, William K. Scott, Mihai G. Netea

Research output: Contribution to journalArticle

Abstract

Background. Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. Methods. A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro-and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients.Results.None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. Conclusions. Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.

Original languageEnglish (US)
Pages (from-to)502-510
Number of pages9
JournalClinical Infectious Diseases
Volume54
Issue number4
DOIs
StatePublished - Feb 15 2012
Externally publishedYes

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Invasive Candidiasis
Candidemia
Cohort Studies
Prospective Studies
Fungemia
Cytokines
Interleukin-10
Single Nucleotide Polymorphism
Genes
Candida
Infection
Interleukin-18
Cytokine Receptors
Total Parenteral Nutrition
Serum
Innate Immunity
Interferons
Dialysis
Blood Cells
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Infectious Diseases
  • Microbiology (medical)

Cite this

Johnson, M. D., Plantinga, T. S., Van De Vosse, E., Velez Edwards, D. R., Smith, P. B., Alexander, B. D., ... Netea, M. G. (2012). Cytokine gene polymorphisms and the outcome of invasive candidiasis: A prospective cohort study. Clinical Infectious Diseases, 54(4), 502-510. https://doi.org/10.1093/cid/cir827

Cytokine gene polymorphisms and the outcome of invasive candidiasis : A prospective cohort study. / Johnson, Melissa D.; Plantinga, Theo S.; Van De Vosse, Esther; Velez Edwards, Digna R.; Smith, P. Brian; Alexander, Barbara D.; Yang, John C.; Kremer, Dennis; Laird, Gregory; Oosting, Marije; Joosten, Leo A B; Van Der Meer, Jos W M; Van Dissel, Jaap T.; Walsh, Thomas J.; Perfect, John R.; Kullberg, Bart Jan; Scott, William K.; Netea, Mihai G.

In: Clinical Infectious Diseases, Vol. 54, No. 4, 15.02.2012, p. 502-510.

Research output: Contribution to journalArticle

Johnson, MD, Plantinga, TS, Van De Vosse, E, Velez Edwards, DR, Smith, PB, Alexander, BD, Yang, JC, Kremer, D, Laird, G, Oosting, M, Joosten, LAB, Van Der Meer, JWM, Van Dissel, JT, Walsh, TJ, Perfect, JR, Kullberg, BJ, Scott, WK & Netea, MG 2012, 'Cytokine gene polymorphisms and the outcome of invasive candidiasis: A prospective cohort study', Clinical Infectious Diseases, vol. 54, no. 4, pp. 502-510. https://doi.org/10.1093/cid/cir827
Johnson MD, Plantinga TS, Van De Vosse E, Velez Edwards DR, Smith PB, Alexander BD et al. Cytokine gene polymorphisms and the outcome of invasive candidiasis: A prospective cohort study. Clinical Infectious Diseases. 2012 Feb 15;54(4):502-510. https://doi.org/10.1093/cid/cir827
Johnson, Melissa D. ; Plantinga, Theo S. ; Van De Vosse, Esther ; Velez Edwards, Digna R. ; Smith, P. Brian ; Alexander, Barbara D. ; Yang, John C. ; Kremer, Dennis ; Laird, Gregory ; Oosting, Marije ; Joosten, Leo A B ; Van Der Meer, Jos W M ; Van Dissel, Jaap T. ; Walsh, Thomas J. ; Perfect, John R. ; Kullberg, Bart Jan ; Scott, William K. ; Netea, Mihai G. / Cytokine gene polymorphisms and the outcome of invasive candidiasis : A prospective cohort study. In: Clinical Infectious Diseases. 2012 ; Vol. 54, No. 4. pp. 502-510.
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abstract = "Background. Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. Methods. A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro-and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients.Results.None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13{\%} of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95{\%} confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. Conclusions. Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.",
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T1 - Cytokine gene polymorphisms and the outcome of invasive candidiasis

T2 - A prospective cohort study

AU - Johnson, Melissa D.

AU - Plantinga, Theo S.

AU - Van De Vosse, Esther

AU - Velez Edwards, Digna R.

AU - Smith, P. Brian

AU - Alexander, Barbara D.

AU - Yang, John C.

AU - Kremer, Dennis

AU - Laird, Gregory

AU - Oosting, Marije

AU - Joosten, Leo A B

AU - Van Der Meer, Jos W M

AU - Van Dissel, Jaap T.

AU - Walsh, Thomas J.

AU - Perfect, John R.

AU - Kullberg, Bart Jan

AU - Scott, William K.

AU - Netea, Mihai G.

PY - 2012/2/15

Y1 - 2012/2/15

N2 - Background. Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. Methods. A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro-and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients.Results.None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. Conclusions. Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.

AB - Background. Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. Methods. A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro-and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients.Results.None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. Conclusions. Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.

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