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

TitleIL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.
Publication TypeJournal Article
Year of Publication2013
AuthorsMeyer NJ, Feng R, Li M, Zhao Y, Sheu C-C, Tejera P, Gallop R, Bellamy S, Rushefski M, Lanken PN, Aplenc R, O'Keefe GE, Wurfel MM, Christiani DC, Christie JD
JournalAm J Respir Crit Care Med
Volume187
Issue9
Pagination950-9
Date Published2013 May 1
ISSN1535-4970
KeywordsAdult, Aged, Case-Control Studies, Cohort Studies, Enzyme-Linked Immunosorbent Assay, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Intensive Care Units, Logistic Models, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-1, Respiratory Distress Syndrome, Adult, Risk, Risk Factors, Severity of Illness Index
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 = 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.

DOI10.1164/rccm.201208-1501OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID23449693
PubMed Central IDPMC3707367
Grant ListGM066946 / GM / NIGMS NIH HHS / United States
HL060290 / HL / NHLBI NIH HHS / United States
HL060710 / HL / NHLBI NIH HHS / United States
HL079063 / HL / NHLBI NIH HHS / United States
HL081619 / HL / NHLBI NIH HHS / United States
HL090021 / HL / NHLBI NIH HHS / United States
HL102254 / HL / NHLBI NIH HHS / United States
K23 HL102254 / HL / NHLBI NIH HHS / United States
L30 HL097857 / HL / NHLBI NIH HHS / United States
R01 GM088566 / GM / NIGMS NIH HHS / United States
RC2HL101770 / HL / NHLBI NIH HHS / United States