title: Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study.
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.
authors.affiliation: Duke University Medical Center, Durham,North Carolina, USA
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez Edwards
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.forename: John C
authors.initials: JC
authors.lastname: Yang
authors.forename: Dennis
authors.initials: D
authors.lastname: Kremer
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Laird
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000368:Aged; D058365:Candidiasis, Invasive / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D002478:Cells, Cultured; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D016207:Cytokines