Interleukin-1 receptor-associated kinase 3 gene associates with susceptibility to acute lung injury

María Pino-Yanes, Shwu Fan Ma, Xiaoguang Sun, Paula Tejera, Almudena Corrales, Jesús Blanco, Lina Pérez-Méndez, Elena Espinosa, Arturo Muriel, Lluis Blanch, Joe G.N. Garcia, Jesús Villar, Carlos Flores

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20 Scopus citations

Abstract

Sepsis is the most common cause of acute lung injury (ALI), leading to organ dysfunction and death in critically ill patients. Previous studies associated variants of interleukin-1 receptor-associated kinase genes (IRAKs) with differential immune responses to pathogens and with outcomes during sepsis, and revealed that increased expression levels of the IRAK3 gene were correlated with poor outcomes during sepsis. Here we explored whether common variants of the IRAK3 gene were associated with susceptibility to, and outcomes of, severe sepsis. After our discovery of polymorphism, we genotyped a subset of seven single-nucleotide polymorphisms (SNPs) in 336 population-based control subjects and 214 patients with severe sepsis, collected as part of a prospective study of adults from a Spanish network of intensive care units. Whereas IRAK3 SNPs were not associated with susceptibility to severe sepsis, rs10506481 showeda significant association with the development of ALI among patients with sepsis (P=0.007).The association remained significant after adjusting for multiple comparisons, population stratification, and clinical variables (odds ratio, 2.50; 95% confidence interval, 1.15-5.47; P = 0.021). By imputation, we revealed three additional SNPs independently associated with ALI (P < 0.01). One of these (rs1732887) predicted the disruption of a putative human-mouse conserved transcription factor binding site, and demonstrated functional effects in vitro (P=0.017). Despite the need for replication in independent studies, our data suggest that common SNPs in the IRAK3 gene may be determinants of sepsis-induced ALI.

Original languageEnglish (US)
Pages (from-to)740-745
Number of pages6
JournalAmerican journal of respiratory cell and molecular biology
Volume45
Issue number4
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

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Keywords

  • Case-control
  • Polymorphism
  • SNP
  • Severe sepsis
  • Toll-like receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Pino-Yanes, M., Ma, S. F., Sun, X., Tejera, P., Corrales, A., Blanco, J., Pérez-Méndez, L., Espinosa, E., Muriel, A., Blanch, L., Garcia, J. G. N., Villar, J., & Flores, C. (2011). Interleukin-1 receptor-associated kinase 3 gene associates with susceptibility to acute lung injury. American journal of respiratory cell and molecular biology, 45(4), 740-745. https://doi.org/10.1165/rcmb.2010-0292OC