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. 2018 Jul 9;6(1):16.
doi: 10.1186/s40635-018-0181-6.

A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome

Natalia Hernandez-Pacheco  1 , Beatriz Guillen-Guio  1 , Marialbert Acosta-Herrera  1   2   3 , Maria Pino-Yanes  1   4   5 , Almudena Corrales  1   4 , Alfonso Ambrós  6 , Leonor Nogales  7 , Arturo Muriel  8 , Elena González-Higueras  9 , Francisco J Diaz-Dominguez  10 , Elizabeth Zavala  4   11 , Javier Belda  12 , Shwu-Fan Ma  13 , Jesús Villar  2   4 , Carlos Flores  14   15 ; GEN-SEP Network
Collaborators, Affiliations

A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome

Natalia Hernandez-Pacheco et al. Intensive Care Med Exp. .

Abstract

Background: 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. We aimed to identify novel genes implicated in sepsis-induced ARDS susceptibility.

Methods: We 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.

Results: Three 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).

Conclusions: We 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.

Keywords: Acute lung injury; Genetic predisposition; Polymorphism; Sepsis.

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Conflict of interest statement

Ethics approval and consent to participate

The study was performed according to The Code of Ethics of the World Medical Association (Declaration of Helsinki), and informed consent was obtained from all patients or from their appropriate surrogates. The Research Ethics Committees of all participant hospitals approved this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Schematic representation of study procedures for gene prioritization for case-control association studies with ARDS susceptibility. Total RNA from left lung tissue from surviving animals of a rodent model of ARDS was used to perform gene expression comparisons among three experimental groups on different mechanical ventilation (MV) strategies. These analyses revealed neuron projection morphogenesis and signaling by vascular endothelial growth factor (VEGF) as differentially deregulated pathways, as well as in independent human genomic data. Among the genes contained in both pathways (9 and 44 genes, respectively), only those with at least one significant SNP (p value ≤ 0.01) in the GWAS of ARDS were prioritized: dynein cytoplasmatic 2, heavy chain 1 (DYNC2H1), fms-related tyrosine kinase-1 (FLT1), integrin, alpha-1 (ITGA1), and peroxiredoxin-6 (PRDX6), the latter was excluded for association analyses because the top SNP was monomorphic in the discovery study
Fig. 2
Fig. 2
Workflow of the study design. Quality control steps performed in each stage for the samples analyzed. Abbreviations: QC quality control, ARDS acute respiratory distress syndrome
See this image and copyright information in PMC

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