COVID-19 Genetics: University of Edinburgh Study Confirms That Genes Are Critical To New COVID-19 Treatments
: Researchers from the University of Edinburgh have identified potential treatments for COVID-19 after the discovery of five genes associated with the most severe form of the disease. The genes: IFNAR2, TYK2, OAS1, DPP9 and CCR2 partially explain why some individuals become desperately sick with COVID-19, while others are not affected.
According to the study team’s abstract, host-mediated lung inflammation is present and drives mortality in critical illness caused by COVID-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.
The study team reported the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study (GWAS) in 2244 critically ill COVID-19 patients from 208 UK intensive care units (ICUs). They identified and replicated novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 ×× 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 ×× 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 ×× 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 ×× 10-8) in the interferon receptor gene IFNAR2.
The team identified potential targets for repurposing of licensed medications: using Mendelian randomization they found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19.
The study results identify robust genetic signals relating to key host antiviral defense mechanisms, and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomized clinical trials will be essential before any change to clinical practice.
The study findings were published in the peer-reviewed journal: Nature https://www.nature.com/articles/s41586-020-03065-y
The current trend is such that genetic evidence is second only to clinical trials as a way to tell which treatments will be effective in a disease. Existing drugs that target the actions of the genes reveal which drugs should be repurposed to treat COVID-19 in clinical trials, experts say.
The genes involved in two molecular processes ie antiviral immunity and lung inflammation were pinpointed.
The breakthrough discovery will help physicians understand how COVID-19 damages lungs at a molecular level.
The study team made the discovery by studying the DNA of 2,700 patients in 208 intensive care units (ICUs) in the UK.
The study team from the GenOMICC consortiuma global collaboration to study genetics in critical illness and c
ompared the genetic information of COVID-19 patients in ICU with samples provided by healthy volunteers from other studies, such as UK Biobank, Generation Scotland and 100,000 Genomes.
The researchers found key differences in five genes of the ICU patients compared with samples provided by healthy volunteers. The genes IFNAR2, TYK2, OAS1, DPP9 and CCR2 can partially explain why some people become desperately sick with COVID-19, while others are not affected.
After having discovered the genes, the study team was then able to predict the effect of drug treatments on patients, because some genetic variants respond in a similar way to particular drugs.
For instance the team showed that a reduction in the activity of the TYK2 gene protects against COVID-19. A class of anti-inflammatory drugs called JAK inhibitors, which includes the drug baricitinib, produces this effect.
The study team also discovered that a boost in the activity of the gene INFAR2 is also likely to create protection, because it is likely to mimic the effect of treatment with interferon ie proteins released by cells of the immune system to defend against viruses.
But experts caution that to be effective, patients might need the treatment early in disease.
The study team says that clinical trials should focus on drugs that target these specific antiviral and anti-inflammatory pathways.
The project's chief investigator and Academic Consultant in Critical Care Medicine and Senior Research Fellow at University of Edinburgh's Roslin Institute, Dr Kenneth Baillie told Thailand Medical News, "This is a stunning realization of the promise of human genetics to help understand critical illness. Just like in sepsis and influenza, in COVID-19, damage to the lungs is caused by our own immune system, rather than the virus itself. Our genetic results provide a roadmap through the complexity of immune signals, showing the route to key drug targets.”
He added, "Study findings immediately highlight which drugs should be at the top of the list for clinical testing. We can only test a few drugs at a time, so making the right choices will save thousands of lives.”
He further added, “This research is only possible because of the generous contribution of the patients themselves and their families, research teams in NHS hospitals across the country, and the generous funding we've received from the public and organizations."
The study team concluded, “We have discovered new and highly plausible genetic associations with critical illness in COVID-19. Some of these associations lead directly to potential therapeutic approaches to augment interferon signaling, antagonize monocyte activation and infiltration into the lungs, or specifically target harmful inflammatory pathways. While this adds substantially to the biological rationale underpinning specific therapeutic approaches, each treatment must be tested in large-scale clinical trials before entering clinical practice.”
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