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|Title||IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Meyer 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|
|Journal||Am J Respir Crit Care Med|
|Date Published||2013 May 1|
|Keywords||Adult, 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|
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.
|Alternate Journal||Am. J. Respir. Crit. Care Med.|
|PubMed Central ID||PMC3707367|
|Grant List||GM066946 / 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