Integrative omics provide biological and clinical insights into acute respiratory distress syndrome.

Autor: Du M; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA.; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China., Garcia JGN; Department of Medicine, University of Arizona, Tucson, AZ, USA., Christie JD; Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Xin J; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China., Cai G; Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA., Meyer NJ; Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Zhu Z; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA., Yuan Q; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA., Zhang Z; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China., Su L; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA., Shen S; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu, China., Dong X; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA.; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu, China., Li H; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA., Hutchinson JN; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA., Tejera P; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA., Lin X; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.; Department of Statistics, Harvard University, Cambridge, MA, USA., Wang M; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. mwang@njmu.edu.cn.; The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, Jiangsu, China. mwang@njmu.edu.cn., Chen F; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. fengchen@njmu.edu.cn.; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu, China. fengchen@njmu.edu.cn., Christiani DC; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA. dchris@hsph.harvard.edu.; Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. dchris@hsph.harvard.edu.
Jazyk: angličtina
Zdroj: Intensive care medicine [Intensive Care Med] 2021 Jul; Vol. 47 (7), pp. 761-771. Date of Electronic Publication: 2021 May 25.
DOI: 10.1007/s00134-021-06410-5
Abstrakt: Purpose: Acute respiratory distress syndrome (ARDS) is accompanied by a dysfunctional immune-inflammatory response following lung injury, including during coronavirus disease 2019 (COVID-19). Limited causal biomarkers exist for ARDS development. We sought to identify novel genetic susceptibility targets for ARDS to focus further investigation on their biological mechanism and therapeutic potential.
Methods: Meta-analyses of ARDS genome-wide association studies were performed with 1250 cases and 1583 controls in Europeans, and 387 cases and 387 controls in African Americans. The functionality of novel loci was determined in silico using multiple omics approaches. The causality of 114 factors potentially involved in ARDS development was assessed using Mendelian Randomization analysis.
Results: There was distinct genetic heterogeneity in ARDS between Europeans and African Americans. rs7967111 at 12p13.2 was functionally associated with ARDS susceptibility in Europeans (odds ratio = 1.38; P = 2.15 × 10 -8 ). Expression of two genes annotated at this locus, BORCS5 and DUSP16, was dynamic but ultimately decreased during ARDS development, as well as downregulated in immune cells alongside COVID-19 severity. Causal inference implied that comorbidity of inflammatory bowel disease and elevated levels of C-reactive protein and interleukin-10 causally increased ARDS risk, while vitamin D supplementation and vasodilator use ameliorated risk.
Conclusion: Our findings suggest a novel susceptibility locus in ARDS pathophysiology that implicates BORCS5 and DUSP16 as potentially acting in immune-inflammatory processes. This locus warrants further investigation to inform the development of therapeutic targets and clinical care strategies for ARDS, including those induced by COVID-19.
Databáze: MEDLINE
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