Nick Lench, PhD, Chief Scientific Officer, Congenica
The world has passed the sobering milestone of over 10 million confirmed cases of COVID-19 and in excess of half a million deaths1. Despite successful containment measures in many countries, the worldwide infection rate continues to rise.
However, clinical and scientific communities have mobilized rapidly to generate and share data to understand how the virus is spread, what symptoms patients display, their response to infection and clinical outcomes. Moreover, the race to develop new vaccines and find effective treatments is gathering pace.
Watch as Dr Nick Lench reviews the current state of knowledge regarding the genetics of COVID-19 and the potential application of pharmacogenetics to patient management and clinical trials. What have we learnt over the last 6-7 months since the COVID-19 outbreak was reported in Wuhan, China? Additionally, are there specific genetic and genomic factors that influence susceptibility and response to infection?
Initial observations have remained consistent: the key risk factors include age (> 55 years), gender (men > women) and co-morbidities (cardiovascular disease, obesity and diabetes). Recent studies in the UK suggest that South Asian men have a significantly higher mortality rate than their white counterparts2.
Another reported risk factor is blood group, with type “O” appearing to have a protective effect and type “A” a susceptibility factor3,4. Much of the current literature is published freely as part of international open access and data sharing policies (rightly and with good intentions); however, the pace of data generation and manuscript submission means that the majority of such published articles are awaiting peer-review. Therefore, results should be treated with scrutiny and conclusions subjected to independent replication and validation.
Understanding the biology of COVID-19
Of particular interest to understanding the biology of SARS-CoV-2 infection and disease progression are seemingly healthy individuals who experience increased mortality and morbidity. Such outliers may have an underlying genetic pre-disposition that influences how the virus enters human epithelial cells and replicates and interacts with the host. One can hypothesize that genetic variation in the SARS-CoV-2 receptor (ACE2 gene) may result in a range of protein structures that binds the SARS-CoV-2 spike protein with different levels of affinity.
Similarly, genetic variation in the TMPRSS2 gene may produce proteins that proteolyze the virus-receptor complex with different levels of efficiency. Such variation should be a consideration when designing vaccines to the viral spike protein. We now know that a new strain of SARS-CoV-2 has evolved with an altered spike protein that enhances viral infectivity and is the predominate strain in Europe5,6.
We can also learn from genetic disorders that mimic the cytokine storm observed in many of the most severely affected patients. Familial haemophagocytic lymphohistiocytosis (FHLH) is one of a group of macrophage activation syndromes characterized by high fever, an over-active immune response, lymphocytopenia and evidence for intravascular coagulation activation. Mutations in over 20 different genes can cause FHLH.
Another class of disorders, the primary immunodeficiency syndromes, represent over 400 distinct chronic single gene disorders that are categorized by recurrent infections and compromised or absent immune response.
Progress being made in COVID-19 genetic research
Identifying novel genetic markers associated with SARS-CoV-2 infection and COVID-19 disease progression and outcomes requires large cohort and population studies. The COVID-19 Host Genetics Initiative is coordinating the analysis of data from over 200 independent (international) registered studies including UK Biobank, UK100KGP (Genomics England) and UK Genetics of Mortality in Critical Care (GenOMICC).
Preliminary findings from some of these studies have already been released showing some interesting suggestive genome-wide associations between respiratory failure and genes involved in the inflammatory cascade4.
Finally, rapid progress is being made towards vaccine production and the identification of novel therapies. Early success has been reported recently for the use of dexamethasone, a well-established anti-inflammatory (gluco-corticosteroid) that has been shown to reduce mortality by approximately one third in critically ill patients7. This represents a significant breakthrough and is the first step in our progress to controlling the symptoms of this devastating disease.
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For researchers investigating COVID-19, the Congenica COVID-19 module enables you to target the genomic factors related to host response with a high-degree of confidence, while saving hundreds of hours of literature review and gene analysis.