RT Journal Article SR Electronic T1 Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 671 OP 680 DO 10.1136/jmedgenet-2012-100972 VO 49 IS 11 A1 Tejera, Paula A1 Meyer, Nuala J A1 Chen, Feng A1 Feng, Rui A1 Zhao, Yang A1 O'Mahony, D Shane A1 Li, Lin A1 Sheu, Chau-Chyun A1 Zhai, Rihong A1 Wang, Zhaoxi A1 Su, Li A1 Bajwa, Ed A1 Ahasic, Amy M A1 Clardy, Peter F A1 Gong, Michelle N A1 Frank, Angela J A1 Lanken, Paul N A1 Thompson, B Taylor A1 Christie, Jason D A1 Wurfel, Mark M A1 O'Keefe, Grant E A1 Christiani, David C YR 2012 UL http://jmg.bmj.com/content/49/11/671.abstract AB Background The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes. Methods We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III). Results In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p<0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p<0.006, Stage II; p<0.05, Stage III). Meta-analysis confirmed these associations. Conclusions Different genetic variants may influence ARDS susceptibility depending on direct versus indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI/ARDS, respectively.