title: Interleukin-1 receptor-associated kinase 3 gene associates with susceptibility to acute lung injury.
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 showed a 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.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pino-Yanes
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.forename: Paula
authors.initials: P
authors.lastname: Tejera
authors.forename: Almudena
authors.initials: A
authors.lastname: Corrales
authors.forename: Jesús
authors.initials: J
authors.lastname: Blanco
authors.forename: Lina
authors.initials: L
authors.lastname: Pérez-Méndez
authors.forename: Elena
authors.initials: E
authors.lastname: Espinosa
authors.forename: Arturo
authors.initials: A
authors.lastname: Muriel
authors.forename: Lluis
authors.initials: L
authors.lastname: Blanch
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000368:Aged; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D007362:Intensive Care Units; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D018805:Sepsis / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D012720:Severity of Illness Index; D013030:Spain; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D014157:Transcription Factors; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases