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Intensive Care Med Exp. 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.

Author information

1
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
2
Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.
3
Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, P.T.S, Granada, Spain.
4
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
5
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain.
6
Intensive Care Unit, Hospital General de Ciudad Real, Ciudad Real, Spain.
7
Intensive Care Unit, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
8
Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain.
9
Intensive Care Unit, Hospital Virgen de La Luz, Cuenca, Spain.
10
Intensive Care Unit, Hospital General de León, León, Spain.
11
Intensive Care Unit, Hospital Clinic Barcelona, Barcelona, Spain.
12
Department of Anesthesiology, Hospital Clínico Universitario, Universidad de Valencia, Valencia, Spain.
13
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, USA.
14
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. cflores@ull.edu.es.
15
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. cflores@ull.edu.es.

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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