Cargando…

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

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 tar...

Descripción completa

Detalles Bibliográficos
Autores principales: Du, Mulong, Garcia, Joe G. N., Christie, Jason D., Xin, Junyi, Cai, Guoshuai, Meyer, Nuala J., Zhu, Zhaozhong, Yuan, Qianyu, Zhang, Zhengdong, Su, Li, Shen, Sipeng, Dong, Xuesi, Li, Hui, Hutchinson, John N., Tejera, Paula, Lin, Xihong, Wang, Meilin, Chen, Feng, Christiani, David C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144871/
https://www.ncbi.nlm.nih.gov/pubmed/34032881
http://dx.doi.org/10.1007/s00134-021-06410-5
_version_ 1783697048981209088
author Du, Mulong
Garcia, Joe G. N.
Christie, Jason D.
Xin, Junyi
Cai, Guoshuai
Meyer, Nuala J.
Zhu, Zhaozhong
Yuan, Qianyu
Zhang, Zhengdong
Su, Li
Shen, Sipeng
Dong, Xuesi
Li, Hui
Hutchinson, John N.
Tejera, Paula
Lin, Xihong
Wang, Meilin
Chen, Feng
Christiani, David C.
author_facet Du, Mulong
Garcia, Joe G. N.
Christie, Jason D.
Xin, Junyi
Cai, Guoshuai
Meyer, Nuala J.
Zhu, Zhaozhong
Yuan, Qianyu
Zhang, Zhengdong
Su, Li
Shen, Sipeng
Dong, Xuesi
Li, Hui
Hutchinson, John N.
Tejera, Paula
Lin, Xihong
Wang, Meilin
Chen, Feng
Christiani, David C.
author_sort Du, Mulong
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00134-021-06410-5.
format Online
Article
Text
id pubmed-8144871
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-81448712021-05-25 Integrative omics provide biological and clinical insights into acute respiratory distress syndrome Du, Mulong Garcia, Joe G. N. Christie, Jason D. Xin, Junyi Cai, Guoshuai Meyer, Nuala J. Zhu, Zhaozhong Yuan, Qianyu Zhang, Zhengdong Su, Li Shen, Sipeng Dong, Xuesi Li, Hui Hutchinson, John N. Tejera, Paula Lin, Xihong Wang, Meilin Chen, Feng Christiani, David C. Intensive Care Med Original 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00134-021-06410-5. Springer Berlin Heidelberg 2021-05-25 2021 /pmc/articles/PMC8144871/ /pubmed/34032881 http://dx.doi.org/10.1007/s00134-021-06410-5 Text en © Springer-Verlag GmbH Germany, part of Springer Nature 2021 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Original
Du, Mulong
Garcia, Joe G. N.
Christie, Jason D.
Xin, Junyi
Cai, Guoshuai
Meyer, Nuala J.
Zhu, Zhaozhong
Yuan, Qianyu
Zhang, Zhengdong
Su, Li
Shen, Sipeng
Dong, Xuesi
Li, Hui
Hutchinson, John N.
Tejera, Paula
Lin, Xihong
Wang, Meilin
Chen, Feng
Christiani, David C.
Integrative omics provide biological and clinical insights into acute respiratory distress syndrome
title Integrative omics provide biological and clinical insights into acute respiratory distress syndrome
title_full Integrative omics provide biological and clinical insights into acute respiratory distress syndrome
title_fullStr Integrative omics provide biological and clinical insights into acute respiratory distress syndrome
title_full_unstemmed Integrative omics provide biological and clinical insights into acute respiratory distress syndrome
title_short Integrative omics provide biological and clinical insights into acute respiratory distress syndrome
title_sort integrative omics provide biological and clinical insights into acute respiratory distress syndrome
topic Original
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144871/
https://www.ncbi.nlm.nih.gov/pubmed/34032881
http://dx.doi.org/10.1007/s00134-021-06410-5
work_keys_str_mv AT dumulong integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT garciajoegn integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT christiejasond integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT xinjunyi integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT caiguoshuai integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT meyernualaj integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT zhuzhaozhong integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT yuanqianyu integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT zhangzhengdong integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT suli integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT shensipeng integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT dongxuesi integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT lihui integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT hutchinsonjohnn integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT tejerapaula integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT linxihong integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT wangmeilin integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT chenfeng integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome
AT christianidavidc integrativeomicsprovidebiologicalandclinicalinsightsintoacuterespiratorydistresssyndrome