Genetic Risk for ARDS of Pulmonary or Extrapulmonary Origin
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.
Two different pathogenic pathways can lead to the development of acute lung injury (ALI) and its more severe manifestation, acute respiratory distress syndrome (ARDS): a direct or pulmonary insult that directly affects lung parenchyma, and/or an indirect or extrapulmonary injury that results from an acute systemic inflammatory response and yields pulmonary endothelial damage. Since this distinction was posed by the American European Consensus Conference (AECC) in 1994, the question of whether ARDS of different origins represents two different syndromes, and the possible clinical implications of this differentiation, have been widely debated. Conflicting results have been reported among different clinical studies, largely due to the fact that the classification of the type of injury that leads to ARDS is not always straightforward. Furthermore, it is possible that direct and indirect insults coexist simultaneously in the same patient, and patients in each category can also present different degrees of severity of lung injury. In spite of these contradictory results, there is a growing body of evidence suggesting that pathophysiological characteristics differ between the two types of primary insults. Clinical data and experimental models support differences in pathophysiology, lung morphology, respiratory mechanics and response to different ventilator strategies and pharmacological agents between ARDS from pulmonary and extrapulmonary origin. Genetic factors are known to play an important role in ARDS development. While several studies have indicated an effect modification by the type of injury in the genetic associations with the risk of ARDS, the potential role of genetics underlying the differences between ARDS resulting from pulmonary and extrapulmonary injury has not been investigated in detail. In this study, we explore the hypothesis that different genetic susceptibility profiles could underlie the development of ARDS from different insults. To identify common genetic variants contributing to the development of ARDS from different origins, we conducted a large-scale genomic association study involving ~2100 genes on a critically ill patient population of 1717 subjects with either direct or indirect lung injury as predisposing conditions for ARDS. Three critically ill populations with severe trauma or pneumonia/pulmonary sepsis as the risk factor for ALI/ARDS were used to validate our primary results.
Abstract and Introduction
Abstract
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.
Introduction
Two different pathogenic pathways can lead to the development of acute lung injury (ALI) and its more severe manifestation, acute respiratory distress syndrome (ARDS): a direct or pulmonary insult that directly affects lung parenchyma, and/or an indirect or extrapulmonary injury that results from an acute systemic inflammatory response and yields pulmonary endothelial damage. Since this distinction was posed by the American European Consensus Conference (AECC) in 1994, the question of whether ARDS of different origins represents two different syndromes, and the possible clinical implications of this differentiation, have been widely debated. Conflicting results have been reported among different clinical studies, largely due to the fact that the classification of the type of injury that leads to ARDS is not always straightforward. Furthermore, it is possible that direct and indirect insults coexist simultaneously in the same patient, and patients in each category can also present different degrees of severity of lung injury. In spite of these contradictory results, there is a growing body of evidence suggesting that pathophysiological characteristics differ between the two types of primary insults. Clinical data and experimental models support differences in pathophysiology, lung morphology, respiratory mechanics and response to different ventilator strategies and pharmacological agents between ARDS from pulmonary and extrapulmonary origin. Genetic factors are known to play an important role in ARDS development. While several studies have indicated an effect modification by the type of injury in the genetic associations with the risk of ARDS, the potential role of genetics underlying the differences between ARDS resulting from pulmonary and extrapulmonary injury has not been investigated in detail. In this study, we explore the hypothesis that different genetic susceptibility profiles could underlie the development of ARDS from different insults. To identify common genetic variants contributing to the development of ARDS from different origins, we conducted a large-scale genomic association study involving ~2100 genes on a critically ill patient population of 1717 subjects with either direct or indirect lung injury as predisposing conditions for ARDS. Three critically ill populations with severe trauma or pneumonia/pulmonary sepsis as the risk factor for ALI/ARDS were used to validate our primary results.
SHARE
