Abstract
BackgroundThe acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units. Previous studies have demonstrated the existence of genetic variants involved in the susceptibility and outcomes of this syndrome. We aimed to identify novel genes implicated in sepsis-induced ARDS susceptibility.MethodsWe first performed a prioritization of candidate genes by integrating our own genomic data from a transcriptomic study in an animal model of ARDS and from the only published genome-wide association study of ARDS study in humans. Then, we selected single nucleotide polymorphisms (SNPs) from prioritized genes to conduct a case-control discovery association study in patients with sepsis-induced ARDS (n = 225) and population-based controls (n = 899). Finally, we validated our findings in an independent sample of 661 sepsis-induced ARDS cases and 234 at-risk controls.ResultsThree candidate genes were prioritized: dynein cytoplasmic-2 heavy chain-1, fms-related tyrosine kinase 1 (FLT1), and integrin alpha-1. Of those, a SNP from FLT1 gene (rs9513106) was associated with ARDS in the discovery study, with an odds ratio (OR) for the C allele of 0.76, 95% confidence interval (CI) 0.58–0.98 (p = 0.037). This result was replicated in an independent study (OR = 0.78, 95% CI = 0.62–0.98, p = 0.039), showing consistent direction of effects in a meta-analysis (OR = 0.77, 95% CI = 0.65–0.92, p = 0.003).ConclusionsWe identified FLT1 as a novel ARDS susceptibility gene and demonstrated that integration of genomic data can be a valid procedure to identify novel susceptibility genes. These results contribute to previous firm associations and functional evidences implicating FLT1 gene in other complex traits that are mechanistically linked, through the key role of endothelium, to the pathophysiology of ARDS.
Highlights
The acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units
Three experimental groups were compared based on the ventilatory approach applied: unventilated spontaneously breathing septic animals (SS), septic animals ventilated with protective mechanical ventilation (MV) (SPV), and septic animals ventilated with injurious MV (SIV)
We studied 429 patients with severe sepsis admitted into a network of intensive care units (ICUs) in Spain who were followed for the development of ARDS (n = 230), according to the definition of the American-European Consensus Criteria [1] and as having moderate or severe ARDS according to the Berlin criteria [25]
Summary
The acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units. Previous studies have demonstrated the existence of genetic variants involved in the susceptibility and outcomes of this syndrome. The acute respiratory distress syndrome (ARDS) is an acute and intense inflammatory process of the lung caused by injury to the alveolar-capillary membrane that results in increased permeability and protein-rich edema. There are different processes that can cause ARDS, such as pneumonia, severe trauma, or blood transfusions [4]; sepsis continues to be the main risk factor precipitating this syndrome in adults [5]. Several studies have demonstrated the influence of the individual’s genetic variation in the susceptibility to ARDS [6, 7]. A number of genes have been proposed as biological candidates for ARDS susceptibility based on gene expression studies in animal or cellular models followed by candidate gene association studies [6]
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