Gene variants tied to increased risk of severe COVID-19 disease

October 15, 2020 – SARS-CoV-2 and its resulting disease, Covid-19 disease, is (still) rattling the world. It still remains largely unknown, at this point in time, which are the infected individuals who fall very seriously, even fatally, ill with Covid-19 disease. Of course, there seem to exist some given risk factors, such as age, gender, pre-existing disease, etc. However, there are infected individuals (i.e., patients) who fulfil all these predisposing factors, but don’t even fall ill or easily recover from the infection by SARS-CoV-2  and/or the symptoms of Covid-19 disease.

How come? Researchers think that there may exist genetic variations that render one patient more vulnerable to i) infection as such, and ii) the course and the severity of the Covid-19 disease in a infected individual. In fact, some recent studies point in these direction. Thus, very recently, according to a Science report, researchers have tied three common gene variants to increased risk of severe COVID-19. In this study, a University of Edinburgh-led team conducted a genome-wide association analysis of more than 2,000 patients with severe COVID-19. As they report in a preprint posted to MedRxiv, the researchers homed in on three loci: one within the DPP9 gene, which encodes dipeptidyl peptidase 9, one within a gene cluster encoding the antiviral restriction enzyme activators OAS1, OAS2, and OAS3, and one in the interferon receptor gene IFNAR2.

Science notes that the IFNAR2 variant the team uncovered is present in about a quarter of Europeans and raises the risk of severe disease by 30 percent. This finding is in line with a recent study which showed that clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal Covid-19, and that in these severe cases an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3– and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening Covid-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection was found. By testing these and other rare variants at these 13 loci, LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies were experimentally defined. Human fibroblasts with mutations affecting this pathway were shown to be vulnerable to SARS-CoV-2. Thus, inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Overall, the findings from both of these studies suggest that rare mutations in interferon genes like IFNAR2 are associated with severe disease and that seemingly a considerable proportion of Europeans (i.e., people of Caucasian descent) may carry such defects, leaving them vulnerable to severe courses of the Covid-19 disease.

Surprising in the present study is certainly the finding that the OAS gene may be involved in severe Covid-19 disease predisposition as the OAS genes encode proteins that activate enzymes that typically break down viral genomes. This means that some people are left more vulnerable to initial virus attacks than others. Whether this applies to attacks by SARS-CoV-2 only, or more general to attacks by any virus remains an open question.

Besides, previous studies have also implicated regions on chromosome 3 and in the ABO blood locus. Overall, these studies help to slowly understand more profoundly the impact of SARS-CoV-2 may have on a given individual, and, in the long run, may also help to tailor anti-viral and/or anti-disease treatments more precisely.

See here a sequence on genetics and susceptibility (predisposition) for Covid-19:

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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