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 = 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. 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 = 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. 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.
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 = 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. 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 = 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. 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.
Authors: Anna L Dixon; Liming Liang; Miriam F Moffatt; Wei Chen; Simon Heath; Kenny C C Wong; Jenny Taylor; Edward Burnett; Ivo Gut; Martin Farrall; G Mark Lathrop; Gonçalo R Abecasis; William O C Cookson Journal: Nat Genet Date: 2007-09-16 Impact factor: 38.330
Authors: Hakon Hakonarson; Struan F A Grant; Jonathan P Bradfield; Luc Marchand; Cecilia E Kim; Joseph T Glessner; Rosemarie Grabs; Tracy Casalunovo; Shayne P Taback; Edward C Frackelton; Margaret L Lawson; Luke J Robinson; Robert Skraban; Yang Lu; Rosetta M Chiavacci; Charles A Stanley; Susan E Kirsch; Eric F Rappaport; Jordan S Orange; Dimitri S Monos; Marcella Devoto; Hui-Qi Qu; Constantin Polychronakos Journal: Nature Date: 2007-07-15 Impact factor: 49.962
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Andrew D Johnson; Robert E Handsaker; Sara L Pulit; Marcia M Nizzari; Christopher J O'Donnell; Paul I W de Bakker Journal: Bioinformatics Date: 2008-10-30 Impact factor: 6.937
Authors: Sherene Shalhub; Christopher E Junker; Scott D Imahara; Michael N Mindrinos; Sharmila Dissanaike; Grant E O'Keefe Journal: J Trauma Date: 2009-01
Authors: Luis A Ortiz; Maria Dutreil; Cheryl Fattman; Amitabh C Pandey; German Torres; Kristina Go; Donald G Phinney Journal: Proc Natl Acad Sci U S A Date: 2007-06-14 Impact factor: 11.205
Authors: John J Arcaroli; John E Hokanson; Edward Abraham; Mark Geraci; James R Murphy; Russell P Bowler; Charles A Dinarello; Lori Silveira; Jeff Sankoff; Daren Heyland; Paul Wischmeyer; James D Crapo Journal: Am J Respir Crit Care Med Date: 2008-10-23 Impact factor: 21.405
Authors: Carolyn S Calfee; Kevin Delucchi; Polly E Parsons; B Taylor Thompson; Lorraine B Ware; Michael A Matthay Journal: Lancet Respir Med Date: 2014-05-19 Impact factor: 30.700
Authors: Gi S Yoon; Sudha Sud; Rahul K Keswani; Jason Baik; Theodore J Standiford; Kathleen A Stringer; Gus R Rosania Journal: Mol Pharm Date: 2015-06-05 Impact factor: 4.939
Authors: Heather Lynn; Xiaoguang Sun; Nancy Casanova; Manuel Gonzales-Garay; Christian Bime; Joe G N Garcia Journal: Antioxid Redox Signal Date: 2019-06-18 Impact factor: 8.401
Authors: Joshua M Diamond; Tatiana Akimova; Altaf Kazi; Rupal J Shah; Edward Cantu; Rui Feng; Matthew H Levine; Steven M Kawut; Nuala J Meyer; James C Lee; Wayne W Hancock; Richard Aplenc; Lorraine B Ware; Scott M Palmer; Sangeeta Bhorade; Vibha N Lama; Ann Weinacker; Jonathan Orens; Keith Wille; Maria Crespo; David J Lederer; Selim Arcasoy; Ejigayehu Demissie; Jason D Christie Journal: Am J Respir Crit Care Med Date: 2014-03-01 Impact factor: 21.405