Beatriz Guillen-Guio1, Jose M Lorenzo-Salazar2, Shwu-Fan Ma3, Pei-Chi Hou3, Tamara Hernandez-Beeftink4, Almudena Corrales5, M Isabel García-Laorden6, Jonathan Jou7, Elena Espinosa8, Arturo Muriel9, David Domínguez8, Leonardo Lorente10, María M Martín11, Carlos Rodríguez-Gallego12, Jordi Solé-Violán13, Alfonso Ambrós14, Demetrio Carriedo15, Jesús Blanco16, José M Añón17, John P Reilly18, Tiffanie K Jones18, Caroline Ag Ittner18, Rui Feng19, Franziska Schöneweck20, Michael Kiehntopf21, Imre Noth3, Markus Scholz22, Frank M Brunkhorst23, André Scherag24, Nuala J Meyer18, Jesús Villar25, Carlos Flores26. 1. Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. 2. Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain. 3. Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA. 4. Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; Research Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain. 5. Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 6. Research Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 7. University of Illinois College of Medicine at Peoria, Peoria, IL, USA. 8. Department of Anesthesiology, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. 9. Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain. 10. Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain. 11. Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. 12. Department of Immunology, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain. 13. Intensive Care Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 14. Intensive Care Unit, Hospital General de Ciudad Real, Ciudad Real, Spain. 15. Intensive Care Unit, Complejo Hospitalario Universitario de León, León, Spain. 16. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain. 17. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Intensive Care Unit, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. 18. Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA. 19. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia PA, USA. 20. Integrated Research and Treatment Center, Jena University Hospital, Jena, Germany. 21. Center for Sepsis Control and Care, Institute of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, Germany; Integrated Biobank Jena, Jena University Hospital, Jena, Germany. 22. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 23. Center for Clinical Studies, Jena University Hospital, Jena, Germany; Paul-Martini-Clinical Sepsis Research Unit, Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. 24. Integrated Research and Treatment Center, Jena University Hospital, Jena, Germany; Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany. 25. Research Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Keenan Research Center for Biomedical Sciences at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada. 26. Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. Electronic address: cflores@ull.edu.es.
Abstract
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.
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.
Authors: Patrick Belvitch; Nancy Casanova; Xiaoguang Sun; Sara M Camp; Saad Sammani; Mary E Brown; Joseph Mascarhenas; Heather Lynn; Djanybek Adyshev; Jessica Siegler; Ankit Desai; Laleh Seyed-Saadat; Alicia Rizzo; Christian Bime; Gajendra S Shekhawat; Vinayak P Dravid; John P Reilly; Tiffanie K Jones; Rui Feng; Eleftheria Letsiou; Nuala J Meyer; Nathan Ellis; Joe G N Garcia; Steven M Dudek Journal: Transl Res Date: 2022-02-15 Impact factor: 10.171
Authors: Ammar J Alsheikh; Sabrina Wollenhaupt; Emily A King; Jonas Reeb; Sujana Ghosh; Lindsay R Stolzenburg; Saleh Tamim; Jozef Lazar; J Wade Davis; Howard J Jacob Journal: BMC Med Genomics Date: 2022-04-01 Impact factor: 3.063