Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin

Tejera, Paula; Meyer, Nuala J.; Chen, Feng; Feng, Rui; Zhao, Yang; O’Mahony, D. Shane; Li, Lin; Sheu, Chau‐Chyun; Zhai, Rihong; Wang, Zhaoxi; Li, Su; Bajwa, Ednan K.; Ahasic, Amy M.; Clardy, Peter; Gong, Michelle N.; Frank, Angela; Lanken, Paul N.; Thompson, B. Taylor; Christie, Jason D.; Wurfel, Mark M.; O’Keefe, Grant E.; Christiani, David C.

doi:10.1136/jmedgenet-2012-100972

Cited by 55 publications

(51 citation statements)

References 70 publications

(65 reference statements)

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“…This a threshold has been applied previously for the IBC array (42), and was chosen to achieve approximately 10 SNPs for replication, given that the IBC chip types approximately 30,000 nonrare polymorphic SNPs in EA subjects (10/30,000 ¼ 3.3 3 10…”

Section: Discussionmentioning

confidence: 99%

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

Meyer

Feng

et al. 2013

Am J Respir Crit Care Med

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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...

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Section: Discussionmentioning

confidence: 99%

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

Meyer

Feng

et al. 2013

Am J Respir Crit Care Med

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“…Several studies have used genomic or proteomic techniques to assess for risk of developing ARDS after direct or indirect lung injury 21–23 . One study of 417 patients with ARDS assessed for single nucleotide polymorphisms (SNP) associated with the risk of developing ARDS 21 .…”

Section: Clinical Differences Between Direct and Indirect Ardsmentioning

confidence: 99%

“…One study of 417 patients with ARDS assessed for single nucleotide polymorphisms (SNP) associated with the risk of developing ARDS 21 . A SNP in POPDC3 was associated with a reduced risk for direct ARDS (OR 0.65).…”

Section: Clinical Differences Between Direct and Indirect Ardsmentioning

confidence: 99%

Clinical and Biological Heterogeneity in Acute Respiratory Distress Syndrome

Shaver

Bastarache

2014

Clinics in Chest Medicine

107

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Synopsis The acute respiratory distress syndrome (ARDS) is a heterogeneous group of illnesses affecting the pulmonary parenchyma with acute onset bilateral inflammatory pulmonary infiltrates with associated hypoxemia. ARDS occurs after two major types of pulmonary injury: direct lung injury affecting the lung epithelium or indirect lung injury disrupting the vascular endothelium. Greater understanding of the differences between direct and indirect lung injury may refine our classification of patients with ARDS and lead to development of new therapeutics targeted at specific subpopulations of patients with ARDS. In this review, we will summarize the differences between direct and indirect causes of ARDS in human patients and then will review current knowledge of the similarities and differences in ARDS pathogenesis based on experimental animal models of direct and indirect lung injury. While the separation between direct and indirect causes of ARDS may be oversimplified, it is a useful approach to advancing our current understanding of the pathogenesis of this complex and often fatal disease.

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“…46 Genomic studies also have identifi ed several candidate genes associated with an increased risk for ARDS, although phenotypic heterogeneity has limited their use in clinical research thus far. 47 , 48 Th ese preliminary results are promising, but no biomarkers have yet found their way into prospective clinical trials to guide the identifi cation of patients vulnerable to ARDS who might benefi t from therapies aimed at prevention.…”

Section: The Checklist For Lung Injury Preventionmentioning

confidence: 99%

Preventing ARDS

Beitler

Schoenfeld

Thompson

2014

CHEST

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Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high.Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges.

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Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin

Cited by 55 publications

References 70 publications

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

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

Clinical and Biological Heterogeneity in Acute Respiratory Distress Syndrome

Preventing ARDS

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