Biological Insights into ARDS May Improve Treatment of COVID-19
Key findings
- This study investigated the genetics of acute respiratory distress syndrome (ARDS) and related molecular factors in Europeans and African-Americans
- In Europeans, rs7967111 at 12p13.2 was identified as a novel functional locus for ARDS susceptibility that affected multiple downstream molecular levels
- BORCS5 and DUSP16 were involved in ARDS development by affecting immune–inflammatory response, and decreased expression of these genes in immune cells of COVID-19 patients correlated with the severity of disease
- Among Europeans, polygenic risk scores based on the results of COVID-19 genome-wide association studies were significantly higher in study subjects with all-cause ARDS than in non-ARDS controls
- Findings about all-cause ARDS seem likely to aid in the development of therapies for COVID-19 ARDS
Treatment of acute respiratory distress syndrome (ARDS) related to severe COVID-19 is still limited to supportive care. By investigating genetic and molecular factors related to all-cause ARDS, David C. Christiani, MD, MPH, physician-investigator in the Pulmonary and Critical Care Medicine Division at Massachusetts General Hospital, Feng Chen, PhD, of Nanjing Medical University, and colleagues have uncovered potential targets for therapeutic development in COVID-19 ARDS.
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Genetics of ARDS
The researchers began by conducting meta-analyses of ARDS genome-wide association studies (GWAS). The cohorts were:
- 983 European ARDS cases and 1,247 European non-ARDS controls from the iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk) consortium
- 269 cases and 338 controls from the European subpopulation of the MESSI (Molecular Epidemiology of Sepsis in the ICU) study
- 141 cases and 222 controls from the African-American subpopulation of MESSI
- 247 cases and 167 controls from a GWAS of ARDS in African Americans by Dr. Christiani and colleagues, published in the American Journal of Respiratory and Critical Care Medicine
To the team's surprise, no single-nucleotide polymorphism (SNP) passed genome-wide significance when the two ancestries were considered together. However, rs7967111 A>G at 12p13.2 in Europeans was significantly associated with ARDS development.
Functional and Pleiotropy Analysis
The rs7967111 variant is located at the third intron of BORCS5, about 20 kb downstream of DUSP16. It seemed to dysregulate those genes in blood and lung tissue by disturbing a cascade of DNA methylation, histone modification, gene expression and metabolites.
Expression and Effect of Susceptibility Genes
- In an in-house dataset of 160 ARDS cases and 142 controls, BORCS5 expression and DUSP16 expression were highly correlated regardless of case status
- Strong correlations were also identified in cell lines, particularly lung cells and immune cells, including pulmonary immune cells
Immune Characteristics of ARDS
- When the researchers profiled the blood transcriptome of the in-house dataset, BORCS5 and DUSP16 were dramatically positively correlated with gamma delta T cells, M2 macrophages and neutrophils, and negatively with CD8+ T cells, regulatory T cells, monocytes and resting mast cells
- In preclinical models, BORCS5 and DUSP16 expression decreased during ARDS development
All-Cause ARDS vs. COVID-19 ARDS
Recent GWAS in COVID-19 have identified three SNPs that seem to be involved in severe disease. All three were associated with all-cause ARDS in this study, and two of them had nominal genome-wide significance.
For each European subject in this study, the researchers calculated a polygenic risk score based on the results of three COVID-19 GWAS that accounted for the severity of the disease. Intriguingly, those scores were significantly higher in ARDS cases than controls.
Moreover, single-cell transcriptome data showed reduced expression of BORCS5 and DUSP16 in dendritic cells from patients with severe COVID-19.
Risk Factors for COVID-19 ARDS
The team performed Mendelian randomization analysis, an epidemiological technique that uses genetic variants to distinguish correlation from causation in observational data. From a list of 114 factors proposed to influence the risk of COVID-19 ARDS, they determined that six have a causal role in all-cause ARDS:
- Increased risk of development—inflammatory bowel disease, immunoglobulin G index level in cerebrospinal fluid, C-reactive protein level, interleukin-10 level
- Decreased risk of progression—daily vitamin D supplementation, use of vasodilators to treat cardiac diseases
It may be possible to leverage these findings to predict susceptibility to ARDS, better understand ARDS pathophysiology and create better treatment strategies for ARDS, including ARDS induced by COVID-19.
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