A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome
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 identif...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2018-07-01
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| Series: | Intensive Care Medicine Experimental |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40635-018-0181-6 |
| _version_ | 1819154280607645696 |
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| author | Natalia Hernandez-Pacheco Beatriz Guillen-Guio Marialbert Acosta-Herrera Maria Pino-Yanes Almudena Corrales Alfonso Ambrós Leonor Nogales Arturo Muriel Elena González-Higueras Francisco J. Diaz-Dominguez Elizabeth Zavala Javier Belda Shwu-Fan Ma Jesús Villar Carlos Flores the GEN-SEP Network |
| author_facet | Natalia Hernandez-Pacheco Beatriz Guillen-Guio Marialbert Acosta-Herrera Maria Pino-Yanes Almudena Corrales Alfonso Ambrós Leonor Nogales Arturo Muriel Elena González-Higueras Francisco J. Diaz-Dominguez Elizabeth Zavala Javier Belda Shwu-Fan Ma Jesús Villar Carlos Flores the GEN-SEP Network |
| author_sort | Natalia Hernandez-Pacheco |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T15:18:34Z |
| format | Article |
| id | doaj.art-e8bdddcb59f14674974a00f9a462b693 |
| institution | Directory Open Access Journal |
| issn | 2197-425X |
| language | English |
| last_indexed | 2024-12-22T15:18:34Z |
| publishDate | 2018-07-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Intensive Care Medicine Experimental |
| spelling | doaj.art-e8bdddcb59f14674974a00f9a462b6932022-12-21T18:21:41ZengSpringerOpenIntensive Care Medicine Experimental2197-425X2018-07-016111310.1186/s40635-018-0181-6A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndromeNatalia Hernandez-Pacheco0Beatriz Guillen-Guio1Marialbert Acosta-Herrera2Maria Pino-Yanes3Almudena Corrales4Alfonso Ambrós5Leonor Nogales6Arturo Muriel7Elena González-Higueras8Francisco J. Diaz-Dominguez9Elizabeth Zavala10Javier Belda11Shwu-Fan Ma12Jesús Villar13Carlos Flores14the GEN-SEP NetworkResearch Unit, Hospital Universitario N.S. de Candelaria, Universidad de La LagunaResearch Unit, Hospital Universitario N.S. de Candelaria, Universidad de La LagunaResearch Unit, Hospital Universitario N.S. de Candelaria, Universidad de La LagunaResearch Unit, Hospital Universitario N.S. de Candelaria, Universidad de La LagunaResearch Unit, Hospital Universitario N.S. de Candelaria, Universidad de La LagunaIntensive Care Unit, Hospital General de Ciudad RealIntensive Care Unit, Hospital Clínico Universitario de ValladolidIntensive Care Unit, Hospital Universitario Rio HortegaIntensive Care Unit, Hospital Virgen de La LuzIntensive Care Unit, Hospital General de LeónCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos IIIDepartment of Anesthesiology, Hospital Clínico Universitario, Universidad de ValenciaDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of ChicagoResearch Unit, Hospital Universitario Dr. NegrinResearch Unit, Hospital Universitario N.S. de Candelaria, Universidad de La LagunaAbstract 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.http://link.springer.com/article/10.1186/s40635-018-0181-6Acute lung injurySepsisPolymorphismGenetic predisposition |
| spellingShingle | Natalia Hernandez-Pacheco Beatriz Guillen-Guio Marialbert Acosta-Herrera Maria Pino-Yanes Almudena Corrales Alfonso Ambrós Leonor Nogales Arturo Muriel Elena González-Higueras Francisco J. Diaz-Dominguez Elizabeth Zavala Javier Belda Shwu-Fan Ma Jesús Villar Carlos Flores the GEN-SEP Network A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome Intensive Care Medicine Experimental Acute lung injury Sepsis Polymorphism Genetic predisposition |
| title | A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome |
| title_full | A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome |
| title_fullStr | A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome |
| title_full_unstemmed | A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome |
| title_short | A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome |
| title_sort | vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome |
| topic | Acute lung injury Sepsis Polymorphism Genetic predisposition |
| url | http://link.springer.com/article/10.1186/s40635-018-0181-6 |
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