IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

Abstract

Rationale: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. Objectives: To identify genetic risk variants for ARDS using large scale genotyping. Methods: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n ¼ 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P , 5 3 10 24 for replication in stage II, a trauma case-control population (n ¼ 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 ¼ 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDSassociated genotype and plasma protein levels. Measurements and Main Results: 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 ¼ 0.81; P ¼ 4.2 3 10 25 ). 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. Conclusions: 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.Keywords: functional genetic polymorphism; acute lung injury; acute respiratory distress syndrome; IL-1 receptor antagonist; replication Acute respiratory distress syndrome (ARDS) is a syndrome characterized by acute bilateral alveolar flooding and severe hypoxemia in the absence of clinical heart failure (1, 2). ARDS afflicts an estimated 190,000 people annually in the United States, and carries a mortality of between 30 and 40% (3). The syndrome can emerge after a variety of potential inciting events, such as sepsis, pneumonia, aspiration, and trauma. However, the risk of ARDS after potential at-risk injuries is not uniform; it appears that individual genetic variation contributes to a patient's susceptibility to ARDS (4, 5). The pathophysiology underlying ARDS remains imprecisely understood, but dysregulated inflammation and altered permeability of the alveolocapillary membrane seem Supported by National Institutes of Health (NIH) grants to fund the study populations, Hospital of the University of Pennsylvania (HL060290, HL079063), Harborview (GM066946), and Massachusetts General Hospital (HL060710). Additional NIH grants RC2HL101770, HL081619, HL090021, and HL102254 supported the genetic and molecular investigations described herein. The genetic determinants of acute respiratory distress syndrome (ARDS) susceptibility remain incompletely u...

A Functional Synonymous Coding Variant in theIL1RNGene Is Associated with Survival in Septic Shock

“…) (12). The largest population, with more than 2,000 subjects, had sepsis as the primary risk factor for ARDS (12).…”

“…The largest population, with more than 2,000 subjects, had sepsis as the primary risk factor for ARDS (12). The IL1RN gene encodes for IL-1 receptor antagonist protein (IL1RA), the naturally occurring antagonist for IL-1a and IL-1b.…”

Latent Class Models Identify Two Subphenotypes in Respiratory Distress Syndrome with Differential Response to Positive End-Expiratory Pressure

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Linking Genetics to ARDS Pathogenesis

“…Several investigators have identifi ed genetic variants in genes implicated in alveolar-capillary barrier integrity, 9 infl ammation, 10 and coagulation as risk factors for ARDS 11 ; however, variants resulting in platelet heterogeneity have not previously been linked to ARDS. Working with the knowledge that thrombocytopenia during critical illness is associated with poor outcomes, 12 and that genome-wide association studies have identifi ed several genetic variants linked to platelet count in the noncritically ill, 13 Wei and colleagues 8 set out to answer several questions.…”