#Sepsis-associated #ARDS in individuals of #European #ancestry: a #genome-wide association study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study

Beatriz Guillen-Guio, MSc, Jose M Lorenzo-Salazar, MSc, Shwu-Fan Ma, PhD, Pei-Chi Hou, PhD, Tamara Hernandez-Beeftink, MSc, Almudena Corrales, LT, M Isabel García-Laorden, PhD, Jonathan Jou, MD, Elena Espinosa, MD, Arturo Muriel, MD, David Domínguez, MD, Leonardo Lorente, MD, María M Martín, MD, Carlos Rodríguez-Gallego, MD, Jordi Solé-Violán, MD, Alfonso Ambrós, MD, Demetrio Carriedo, MD, Jesús Blanco, MD, José M Añón, MD, John P Reilly, MD, Tiffanie K Jones, MD, Caroline AG Ittner, PhD, Rui Feng, PhD, Franziska Schöneweck, MSc, Michael Kiehntopf, MD, Imre Noth, MD, Markus Scholz, PhD, Frank M Brunkhorst, MD, André Scherag, PhD, Nuala J Meyer, MD, Jesús Villar, MD, Carlos Flores, PhD

Published: January 23, 2020 / DOI: https://doi.org/10.1016/S2213-2600(19)30368-6

 

Summary

Background

Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.

Methods

We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008–Nov 30, 2017; USA) and the VISEP (April 1, 2003–June 30, 2005) and MAXSEP (Oct 1, 2007–March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.

Findings

We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41–0·91, p=5·18 × 10 −8) located within the Fms-related tyrosine kinase 1 ( FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A ( VEGFA; OR 0·55, 95% CI 0·41–0·73; p=4·69 × 10 −5).

Interpretation

A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.

Funding

Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.

Keywords: ARDS; Sepsis; Genetics.

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Published by

Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.