Host genomics and COVID-19: where are we now?
25 October 2021
COVID-19 can have severe effects on even apparently low-risk individuals, and it has become clear that host factors affecting the risk of infection and disease progression include genomics.
The COVID-19 pandemic has created unprecedented challenges for health systems, pushing evidenced-based medicine to its limits. Researchers have been applying host genomics approaches to unpick the biology of COVID-19, better understand risk and identify promising treatment opportunities.
In the UK, as the new UK Health Security Agency (UKHSA) becomes operational, genomics will certainly play a central role in future pandemic preparedness. This should not be limited to genomic sequencing and analysis of infectious disease agents (pathogens), important as this undoubtedly is. Host genomics also has the potential to be an invaluable tool for understanding the biology underpinning differences in response to an infectious disease, identifying at-risk populations and guiding treatment decisions. The UKHSA should consider how host genomics may support their wider efforts to prepare for the future.
The COVID-19 Host Genomics Initiative (COVID-19 HGI) is an international network of researchers collaborating to map host genetic factors that affect COVID-19 susceptibility and disease severity. This huge study involves nearly 50,000 COVID-19 patients (with a reported SARS-CoV-2 infection, COVID-19 hospitalisation or critical illness) and more than two million controls with an unknown COVID-19 history.
Researchers identified regions of the human genome significantly associated with either SARS-CoV-2 infection or severe COVID-19 disease. Some of these were known to be linked with lung-related or autoimmune conditions. For instance, genetic differences in the TYK2 gene are known to be protective against autoimmune diseases such as rheumatoid arthritis and psoriasis. Additional transcriptomics research has demonstrated that reduced TYK2 activity is protective against COVID-19, making this one of the more promising drug target candidates identified through host genomics research. Other gene variants had been previously linked to an increased risk of interstitial lung disease (a group of diseases that cause scarring of the lungs), further highlighting the role of lung-related pathways in severe COVID-19 cases.
Targets for treatments
The COVID-19 HGI study has also demonstrated the importance of having a diverse population to identify novel genomic associations. Two regions linked to COVID-19 were only identified in individuals with East Asian or South Asian ancestry; one, the FOXP4 gene, is a compelling candidate for potential new treatments.
Meanwhile, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) UK trial has been enormously successful identifying potential treatments for patients hospitalised with COVID-19. One of the therapies being investigated is baricitinib, an immunomodulatory drug currently used in the treatment of rheumatoid arthritis, first identified using machine learning. Host genomics has strengthened the evidence for this treatment. Baricitinib inhibits a family of proteins including the gene, TYK2, with the combined actions of this treatment resulting in reduced expression of TYK2. It is hoped that this treatment may prove effective, which would further support the host genetics approach as a method for identifying and building evidence for candidate treatment targets for infectious diseases.
Changing landscape for pandemic preparedness in the UK
In the UK, the final stages of the transition of infectious disease control functions from Public Health England and NHS Track & Trace into the new UK Health Security Agency (UKHSA) has been completed as of the 1st October. The UK Government recognises that future threats from infectious disease and other external health threats will be different. The UKHSA aims to be a global leader in terms of pandemic preparedness by bringing together national public health science and response capabilities, including cutting edge analytics and genomics surveillance, to ensure a rapid and robust, science-informed response to infectious diseases and other external health threats in the future. Host genomics should certainly form part of this capability, since it is a key tool for the rapid identification of key biological features of new and emerging diseases, making it possible to identify those most at risk and potential targets for treatment.
What next for COVID-19 and host genomics?
This is a very new area of research, with many questions as yet unanswered. Host genomics is already informing the evidence base for therapeutic development, by enabling rapid identification of key biological associations, but the power of such studies will be limited by the number of cases of a disease available for scrutiny. The additional potential of host genomics to help identify individuals at high risk of severe disease may be even harder to realise in practice. It is not clear how this would be achieved without genomic data being more widely available and linked to health records. Increasing the diversity of health and genomic data for research is clearly important for host genomics, and future work will continue to build on this need, including the Genomics England Diverse Data Initiative and the Our Future Health study.
Meanwhile, COVID-19 HGI wants to build on their work looking at severe COVID-19 to address further questions left in the wake of the pandemic. One key area being explored is long COVID, a syndrome where some patients continue to suffer with persistent symptoms (sometimes severe) after the acute phase of COVID-19 infection. COVID-19 HGI have formed an international work group to explore the role that host genomics may have in this complex syndrome, whether it may help predict the risk of long-COVID in acute disease patients, and if it may suggest interventions to prevent it.
Whilst the pressing health questions posed by the COVID-19 pandemic have pushed host genomics into the spotlight, there is undoubtedly potential for this type of research to become a core tool in untangling the biology of a wide range of infectious diseases – those already with us, and the unknown threats of the future.