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Meta-Analyses Hint at Severe COVID-19 Risk Factors, Ties to Autoimmune Disease

NEW YORK – Studies by independent research teams have flagged the genetic variants, genes, and pathways that appear to contribute to — or protect against — severe forms of COVID-19, including variants involved in autoimmune conditions such as systemic lupus erythematosus (SLE).

"These results add to the growing evidence that there are alleles in the human genome that provide protection against viral infection yet are risk [factors] for autoimmune disease," co-senior authors Timothy Vyse and David Morris, a medical and molecular genetics researcher at King's College London, and their colleagues wrote in the first of the studies, published in PLOS Genetics on Thursday.

There, the investigators brought together summary association data from several large, published GWAS involving SLE or severe COVID-19 cases and controls, including data generated through the COVID-19 Host Genetics Initiative, for genome-wide association study meta-analyses and cross-trait meta-analyses. The study included a focus on SLE, they explained, since past studies suggest that genetic risk of the autoimmune condition has been linked to intracellular viral sensing and enhanced interferon gene activity.

With these approaches, the team highlighted variants associated with severe SARS-CoV-2 infections that appeared to protect against SLE risk, including a severe COVID-19-linked locus in and around the Janus kinase enzyme-coding gene TYK2, known for contributing to type I interferon pathway activity and viral infection responses.

Likewise, severe COVID-19 risk variants corresponding with reduced expression of the inflammation-related phosphodiesterase enzyme-coding gene PDE4A appeared to protect against SLE risk.

On the other hand, the researchers reported, a chromosome 12 risk SNP falling at a multi-tissue expression quantitative trait locus for the "C-type lectin domain family 1 member A" gene CLEC1A — known for its role in anti-fungal immunity and cell signaling — was linked to lower-than-usual CLEC1A expression and increased risk of both SLE and severe COVID-19.

"Our results indicate that there are shared genetic effects between the autoimmune disease SLE and the clinical consequences of COVID-19," the authors reported, noting that "[f]urther investigation into the genetic correlation between SLE and severe COVID-19 will help explain the genetic basis of both diseases, which may be in part due to variation in response to viral infection."

In a related paper appearing in PLOS Genetics, members of the COVID-19 Host Genetics Initiative and other international consortia present findings from their own meta-analysis, which focused on rare variants corresponding with severe COVID-19 at the individual variant or gene level.

Using exome or whole-genome sequence data for 5,085 individuals with severe COVID-19 and nearly 572,000 control individuals enrolled in 21 research cohorts across a dozen countries, the researchers unearthed rare severe COVID-19-related variants located in interferon genes and in an X chromosome toll-like receptor gene TLR7, which codes for an innate viral immunity-related protein that prompts enhanced type 1- and type 2 interferon activity in response to single-stranded RNA viruses such as SARS-CoV-2.

Severe COVID-19 risk appeared to be more than five times higher in individuals with deleterious rare variants in TLR7, the authors estimated, consistent with prior research linking TLR7 to severe forms of disease. Unlike some other contributors to severe SARS-CoV-2 infections, they noted that the effect of these variants was consistent between males and females.

Together, these and other findings "further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights," senior and corresponding author Brent Richards, CEO and founder of the Montreal-based firm 5 Prime Sciences, and a researcher at McGill University and Jewish General Hospital, and his colleagues wrote.

The results also revealed rare variants in new and known risk genes involved in everything from ABO blood group type to microtubule function and dynamics within cells, the researchers explained, noting that the rare variant findings "underline the fact that future genome-wide studies of rare variants will require considerably larger sample size, but our work provides a roadmap for such collaborative efforts."