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IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.

ABSTRACT: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete.To identify genetic risk variants for ARDS using large scale genotyping.A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 × 10(-4) for replication in stage II, a trauma case-control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS-associated genotype and plasma protein levels.A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 × 10(-5)). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN.The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.

SUBMITTER: Meyer NJ

PROVIDER: S-EPMC3707367 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.

Meyer Nuala J NJ Feng Rui R Li Mingyao M Zhao Yang Y Sheu Chau-Chyun CC Tejera Paula P Gallop Robert R Bellamy Scarlett S Rushefski Melanie M Lanken Paul N PN Aplenc Richard R O'Keefe Grant E GE Wurfel Mark M MM Christiani David C DC Christie Jason D JD

American journal of respiratory and critical care medicine 20130501 9

<h4>Rationale</h4>Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete.<h4>Objectives</h4>To identify genetic risk variants for ARDS using large scale genotyping.<h4>Methods</h4>A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) ar ...[more]

PMID: 23449693

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Project description:BACKGROUND:There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model. METHODS:Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for "functional metabolites", which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of "functional metabolites" in the lung injury and mortality caused by the respiratory disorder. RESULTS:The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS. CONCLUSION:Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine. TRIAL REGISTRATION:Chinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4.

Dataset Information

IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.

Publications

IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.

Similar Datasets

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