A new study from the GenOMICC (Genetics of Mortality in Critical Care) consortium has provided further details on the genetic causes contributing to severe COVID-19, highlighting a range of genes involved in the immune response and inflammation.
Since the beginning of the COVID-19 pandemic, clinicians and researchers have been puzzled by the differences in disease severity experienced by patients. While some have no or mild symptoms, others can be hospitalised with severe disease affecting a range of organ systems. Taking into account mitigating factors such as age, sex and underlying health conditions only partly explains these differences. Host genomics studies – which explore whether genetic variation in patients’ genomes could explain why some patients fall seriously ill with COVID-19 – have shown that genes involved in anti-viral immune responses and inflammation can play a role.
Building the picture of severe disease
The latest study used whole genome sequencing in 7,491 critically ill patients and compared these genomes to 48,400 controls (mostly healthy or with mild COVID-19). The research team used genome- and transcriptome-wide association studies to find genetic variants associated with severe COVID-19 disease, and whether changes in gene expression were also having an effect.
They found 23 genetic changes associated with different stages of the disease including establishment of the infection, replication of the virus in the body and lung damage caused by inflammation, which contributes to respiratory failure. This work builds on previous studies by GenOMICC, confirming previous genetic associations with disease and confirming new ones.
Key changes were found in genes that are important for immune system function. Five of the variants were within genes involved in interferon signalling, including IL10RB and PLSCR1. Changes in these genes can trigger weaker immune responses to early infection, which aren’t as effective in stopping replication of the virus, which can allow it to spread within the patient. Other genetic changes, e.g. in BCL11A, affect the normal development of cells within the immune system.
The other broad group of genetic changes found have an impact on the development of lung inflammation and blood clots. These include potential roles for the SELE, ICAM5, CD209 genes, and coagulation factor F8. Some of these genes are potential drug targets so provide valuable information to researchers looking for new ways to treat severe COVID-19.
Impact on patients
These results are important because they provide more detail on why some patients fall seriously ill, and what could be done to help them. They also show that a range of genetic factors and mechanisms can lead to serious illness. Understanding these differences could help with decisions around potential treatment options, for example using drugs to help reduce inflammation in patients with genetic variants in immune response genes.
While the pandemic is slowing down in some countries, people are still being hospitalised with severe disease, including in the UK. There will be a need for further advances in treatment options for these patients for some time to come. Bringing the results of studies like this into clinical practice will require clinical trials to explore how and when to carry out genetic testing on critically ill patients and what to do with that genetic information, including investigating potential drugs to manage severe symptoms, based on a patient’s genetic profile.
Host genomics is a growing and important area of research, and demonstrates the power of genomic investigations in supporting the management of infectious diseases. The work of GenOMICC, and others, will not only have an impact on patients affected with COVID-19, but will also increase our knowledge of the complex genetic factors that underpin human responses to infection.