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Posted On: 03/08/2022 8:49:31 AM
Post# of 148876
aerzteblatt.de
quote:
"Edinburgh - Genome analyses of nearly 7,500 intensive care patients show that variants in at least 16 genes help determine whether infection with SARS-CoV-2 leads to a life-threatening illness or whether it remains a mild cold. The findings, presented in Nature (2022; DOI: 10.1038/s41586-022-04576-6), confirm the suggestion that a rapid response by the innate immune system is critical to the progression of the disease.
The GenOMICC ("Genetics of Susceptibility and Mortality in Critical Care"
consortium began sequencing the genomes of critical care patients in 2015 to identify genetic causes of susceptibility to disease. Researchers have focused on COVID-19 since the early 2000s, and to date, the genomes of 7,491 patients treated in 224 intensive care units in the United Kingdom have been decoded. The results were compared with 46,770 participants in the 100,000 Genomes Project, completed in 2018, which decoded the genomes of patients with rare diseases or cancer. In addition, another 1,630 patients with mild covid disease were studied.
The team led by Kenneth Baillie of the University of Edinburgh found variants in 16 genes, many of which encode components of the immune system. This confirms the suspicion that the course of infection with SARS-CoV-2 is strongly influenced by the immune system, with the innate immune system apparently playing a key role.
Of the 16 genes involved, 5 alone are involved in interferon signaling. These include a likely destabilizing amino acid substitution in the ligand IFNA10 and the presumably reduced expression of a subunit of its receptor IFNAR2. Signal transduction occurs via a kinase whose gene TYK2 is also more frequently variant in COVID-19 intensive care patients.
Another missense variant was found in the gene IL10RB, which encodes a receptor for type III interferons (lambda). The 5th altered gene PLSCR1 encodes the enzyme phospholipid scramblase 1, which is involved in the interferon response in the nucleus. These results suggest that a delayed interferon response weakens the initial defense against viruses. The viruses could then multiply unhindered, resulting in an excessive inflammatory response.
Here, too, the researchers found mutations. Among them was a variant in the gene BCL11A, which is required for the formation of B and T lymphocytes. Variants in the gene TAC4 could hinder the formation of B cells and antibodies. Another mutation was located near the gene CSF2, which contains information for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is already being investigated as a target for COVID-19 treatment.
Another mutation is in the gene MUC1, which is responsible for the production of mucin. This could mean that disturbances in mucin production favor a severe course of COVID-19.
There could also be an interesting connection to coagulation factor VIII (whose deficiency is known to be the cause of hemophilia A) or to the gene PDGFRL, which influences platelet function. Both could help explain why there is increased blood clotting in COVID-19. Other disorders were found in cell adhesion molecules (SELE, ICAM5, CD209), through which immune cells communicate with each other.
On the one hand, the gene variants provide important insights into the errors of the immune system that promote the development of a lethal disease. On the other hand, they may provide ideas for new therapies. On the other hand, a genetic test that could be used to test whether people will contract COVID-19 if they are infected with SARS-CoV-2 is not expected. © rme/aerzteblatt.de"
endquote
WUM
Translated with www.DeepL.com/Translator (free version)
quote:
"Edinburgh - Genome analyses of nearly 7,500 intensive care patients show that variants in at least 16 genes help determine whether infection with SARS-CoV-2 leads to a life-threatening illness or whether it remains a mild cold. The findings, presented in Nature (2022; DOI: 10.1038/s41586-022-04576-6), confirm the suggestion that a rapid response by the innate immune system is critical to the progression of the disease.
The GenOMICC ("Genetics of Susceptibility and Mortality in Critical Care"
consortium began sequencing the genomes of critical care patients in 2015 to identify genetic causes of susceptibility to disease. Researchers have focused on COVID-19 since the early 2000s, and to date, the genomes of 7,491 patients treated in 224 intensive care units in the United Kingdom have been decoded. The results were compared with 46,770 participants in the 100,000 Genomes Project, completed in 2018, which decoded the genomes of patients with rare diseases or cancer. In addition, another 1,630 patients with mild covid disease were studied. The team led by Kenneth Baillie of the University of Edinburgh found variants in 16 genes, many of which encode components of the immune system. This confirms the suspicion that the course of infection with SARS-CoV-2 is strongly influenced by the immune system, with the innate immune system apparently playing a key role.
Of the 16 genes involved, 5 alone are involved in interferon signaling. These include a likely destabilizing amino acid substitution in the ligand IFNA10 and the presumably reduced expression of a subunit of its receptor IFNAR2. Signal transduction occurs via a kinase whose gene TYK2 is also more frequently variant in COVID-19 intensive care patients.
Another missense variant was found in the gene IL10RB, which encodes a receptor for type III interferons (lambda). The 5th altered gene PLSCR1 encodes the enzyme phospholipid scramblase 1, which is involved in the interferon response in the nucleus. These results suggest that a delayed interferon response weakens the initial defense against viruses. The viruses could then multiply unhindered, resulting in an excessive inflammatory response.
Here, too, the researchers found mutations. Among them was a variant in the gene BCL11A, which is required for the formation of B and T lymphocytes. Variants in the gene TAC4 could hinder the formation of B cells and antibodies. Another mutation was located near the gene CSF2, which contains information for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is already being investigated as a target for COVID-19 treatment.
Another mutation is in the gene MUC1, which is responsible for the production of mucin. This could mean that disturbances in mucin production favor a severe course of COVID-19.
There could also be an interesting connection to coagulation factor VIII (whose deficiency is known to be the cause of hemophilia A) or to the gene PDGFRL, which influences platelet function. Both could help explain why there is increased blood clotting in COVID-19. Other disorders were found in cell adhesion molecules (SELE, ICAM5, CD209), through which immune cells communicate with each other.
On the one hand, the gene variants provide important insights into the errors of the immune system that promote the development of a lethal disease. On the other hand, they may provide ideas for new therapies. On the other hand, a genetic test that could be used to test whether people will contract COVID-19 if they are infected with SARS-CoV-2 is not expected. © rme/aerzteblatt.de"
endquote
WUM
Translated with www.DeepL.com/Translator (free version)
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